Clinical Ophthalmic Oncology Retinal Tumors 3rd Ed

Clinical Ophthalmic
Oncology
Retinal Tumors
Arun D. Singh
Bertil E. Damato
Editors
Third Edition
123
Clinical Ophthalmic Oncology
Arun D. Singh • Bertil E. Damato
Editors
Clinical Ophthalmic
Oncology
Retinal Tumors
Third Edition
Editors
Arun D. Singh Bertil E. Damato
Cleveland Clinic Foundation University of Oxford
Cole Eye Institute Oxford, UK
Cleveland Clinic Foundation
Cleveland, OH
USA
ISBN 978-3-030-04112-0 ISBN 978-3-030-04113-7 (eBook)

https://doi.org/10.1007/978-3-030-04113-7
Library of Congress Control Number: 2019933400
© Springer Nature Switzerland AG 2019

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Preface
Ophthalmic tumors are rare and diverse so their diagnosis can be quite com-
plex. Treatment usually requires special expertise and equipment and in many
instances is controversial. The field is advancing rapidly, because of acceler-
ating progress in tumor biology, pharmacology, and instrumentation.
Increasingly, the care of patients with an ocular or adnexal tumor is provided
by a multidisciplinary team, consisting of ocular oncologists, general oncolo-
gists, radiotherapists, pathologists, psychologists, and other specialists.
For all these reasons, we felt that there was a need for the new edition of
the textbook providing a balanced view of current clinical practice. Although
each section of Clinical Ophthalmic Oncology, Third Edition, now represents
a standalone volume, each chapter has a similar layout with boxes that high-
light the key features, tables that provide comparison, and flow diagrams that
outline therapeutic approaches.
The enormous task of editing a multi-author, multivolume textbook could
not have been possible without the support and guidance by the staff at
Springer: Caitlin Prim, Melanie Zerah, ArulRonika Pathinathan, and Karthik
Rajasekar. Michael D. Sova kept the pressure on to meet the production
deadlines.
It is our sincere hope that our efforts will meet the high expectation of the
readers.
Cleveland, OH, USA Arun D. Singh

Oxford, UK Bertil E. Damato
v
Acknowledgements
To my parents who educated me beyond their means, my wife Annapurna,

and my children, Nakul and Rahul, who make all my efforts worthwhile
Arun D. Singh.
To my family, Frankanne, Erika, Stephen, and Anna Bertil E. Damato.
vii
Contents
1 Classification of Retinal and Retinal Pigment Epithelium

Tumors�� 1
Ehud Reich, Caroline Thaung, and Mandeep S. Sagoo
2 Coats’ Disease�� 5
Thomas M. Aaberg Jr. and Liliya Shevchenko
3 Retinal Vascular Tumors �� 19
Sachin M. Salvi, Paul A. Rundle, Ian Rennie,
and Arun D. Singh
4 Retinal Astrocytic Tumors�� 39
Christopher Seungkyu Lee, Sungchul Lee, and Arun D. Singh
5 Retinal Pigment Epithelial Tumors�� 51
Elias I. Traboulsi, Matteo Scaramuzzi, and Arun D. Singh
6 Tumors of the Ciliary Epithelium�� 71
Javier Elizalde, María de la Paz, Rafael I. Barraquer,
and Arun D. Singh
7 Primary Central Nervous System and Retinal
Lymphoma�� 83
Mary E. Aronow, Manmeet S. Ahluwalia,
David M. Peereboom, and Arun D. Singh
8 Retinal Metastatic Tumors�� 101
Peter H. Tang, Lejla Vajzovic, and Prithvi Mruthyunjaya
9 Neuro-oculocutaneous Syndromes (Phakomatoses) �� 115
Elaine Binkley, Elias I. Traboulsi, and Arun D. Singh
10 Ocular Paraneoplastic Diseases�� 147
Ilya Leskov and Arun D. Singh
Index�� 165
ix
Editors and Contributors
Editors
Arun D. Singh, MD Department of Ophthalmic Oncology, Cole Eye

Institute, Cleveland Clinic, Cleveland, OH, USA
Bertil E. Damato, MD, PhD, FRCOphth University of Oxford,
Oxford, UK
Contributors
Thomas M. Aaberg Jr, MD Department of Ophthalmology, Retina

Specialists of Michigan, Michigan State University, Spectrum Health, Grand
Rapids, MI, USA
Manmeet S. Ahluwalia, MD The Rose Ella Burkhardt Brain Tumor &
Neuro-Oncology Center, Cleveland Clinic, Cleveland, OH, USA
Mary E. Aronow, MD Massachusetts Eye and Ear, Ocular Melanoma
Center and Retina Service, Harvard Medical School, Boston, MA, USA
Rafael I. Barraquer, MD, PhD Centro de Oftalmología Barraquer,
Barcelona, Spain
Elaine Binkley, MD Department of Ophthalmology, Cole Eye Institute
(i32), Cleveland Clinic Foundation, Cleveland, OH, USA
Maria de la Paz, MD, PhD Centro de Oftalmología Barraquer, Barcelona,
Spain
Javier Elizalde, MD, PhD Centro de Oftalmología Barraquer, Barcelona,
Spain
Christopher Seungkyu Lee, MD, PhD Department of Ophthalmology,
Severance Hospital, Yonsei University, College of Medicine, Seoul, South
Korea
Sungchul Lee, MD, PhD Department of Ophthalmology, Severance
Hospital, Yonsei University, College of Medicine, Seoul, South Korea
xi
xii Editors and Contributors
Ilya Leskov, MD Department of Ophthalmic Oncology, Cole Eye Institute,

Cleveland Clinic Foundation, Cleveland, OH, USA
Prithvi Mruthyunjaya, MD, MHS Department of Ophthalmology, Byers
Eye Institute, Stanford University School of Medicine, Palo Alto, CA, USA
David M. Peereboom, MD, FACP The Rose Ella Burkhardt Brain Tumor &
Neuro-Oncology Center, Cleveland Clinic, Cleveland, OH, USA
Ehud Reich, MD Department of Ophthalmology and Davidoff Center for
Oncology, Rabin Medical Center/Sackler Medical School, Tel Aviv
University, Petach Tikva, Israel
Ian Rennie, FRCOphth Sheffield Ocular Oncology Service, Royal
Hallamshire Hospital, Sheffield, UK
Paul A. Rundle, FRCOphth Sheffield Ocular Oncology Service, Royal
Mandeep S. Sagoo, MB, PhD, FRCOphth, FRCS (Ed) Department of
Ocular Oncology, NIHR Biomedical Research Centre for Ophthalmology at
Moorfields Eye Hospital and UCL Institute of Ophthalmology, London, UK
Sachin M. Salvi, FRCOphth Sheffield Ocular Oncology Service, Royal
Matteo Scaramuzzi, MD Department of Pediatric Ophthalmology and
Strabismus, Center for Genetic Eye Diseases, Cole Eye Institute, Cleveland
Clinic Foundation, Cleveland, OH, USA
Liliya Shevchenko, DO Department of Ophthalmology/Vitreoretinal
Disease, Retina Specialists of Michigan, Grand Rapids, MI, USA
Peter H. Tang, MD, PhD Department of Ophthalmology, Byers Eye
Institute, Stanford University School of Medicine, Palo Alto, CA, USA
Caroline Thaung, FRCOphth, FRCPath, DPhil Department of Eye
Pathology, UCL Institute of Ophthalmology, London, UK
Elias I. Traboulsi, MD Department of Pediatric Ophthalmology and Strabismus,
Center for Genetic Eye Diseases, Cole Eye Institute (i-32), Cleveland Clinic
Foundation, Cleveland, OH, USA
Lejla Vajzovic, MD Duke University Eye Center, Durham, NC, USA
Classification of Retinal
and Retinal Pigment Epithelium
1
Tumors
Ehud Reich, Caroline Thaung,
and Mandeep S. Sagoo
Introduction prognostication. Yet classification can be confus-

ing due to multiple notions about the purposes
Tumor classification is important as it creates a and meaning of modern classifications, more
common terminology that allows clinicians and recently due to the accumulation of emerging
researchers to accurately communicate, thus molecular and genetic results.
facilitating diagnosis by helping the clinician to Tumors of the retina or retinal pigment epithe-
include all conditions that are relevant in a dif- lium can be classified in many ways. There is no
ferential diagnosis. Classification allows us to “gold standard” classification, as new technology
draw historical, international, or multicenter clin- shifts the extent of knowledge and challenges
ical and biological comparisons, thus improving previous classifications. Overall, classification is
our ability to understand the natural course of an organization of everything in a domain by
tumors and facilitate research into new treat- hierarchical groups, according to features gener-
ments. In this chapter, the term “tumor” is used in alizable to the members of the groups [1].
its broadest sense as a mass without implication Clinical classifications usually refer to the
to its pathogenesis or its neoplastic or malignant lists of primary tumors that are known to occur
properties. at a specific anatomical location. This proves a
Classification allows communication between very useful tool for the clinician encountering a
surgeons, oncologists, and pathologists in treat- patient with a new lesion. The drawback is that
ment planning and assessment of treatment out- this schema is not purely a taxonomic classifica-
comes, as well as future treatment options and tion per definition because it includes tumors
that are clinically, biologically, and histologi-
E. Reich cally unrelated. It also creates repetition. Other
Department of Ophthalmology and Davidoff Center classifications differentiate by various schema,
for Oncology, Rabin Medical Center/Sackler Medical such as cell type, genetic or metabolic varia-
School, Tel Aviv University, Petach Tikva, Israel
tions, or indeed benign versus malignant ele-
C. Thaung ments within a tumor type.
Department of Eye Pathology, UCL Institute
of Ophthalmology, London, UK The tumor-node-metastasis (TNM) classifica-
tion has recently been modified (eighth edition)
M. S. Sagoo (*)
Department of Ocular Oncology, NIHR Biomedical and is another system that aids us in trying to
Research Centre for Ophthalmology at Moorfields unify our discussion but covers only malignant
Eye Hospital and UCL Institute of Ophthalmology, tumors, status, and spread [2]. The data col-
London, UK
lected with the TNM system allows us better
e-mail: [email protected]
© Springer Nature Switzerland AG 2019 1

A. D. Singh, B. E. Damato (eds.), Clinical Ophthalmic Oncology,
https://doi.org/10.1007/978-3-030-04113-7_1
2 E. Reich et al.
Table 1.1 Tumors of the retina and retinal pigment epithelium (RPE)
Primary/
Site secondary Tissue type Entities
Retinal Primary Vascular Prenatala Retinal cavernous hemangioma
Arteriovenous malformations (retinal
racemose hemangioma)
Postnatal Retinal capillary hemangioma
Retinal vasoproliferative tumorb
“Primitive” Retinoblastoma
Retinoma/retinocytoma
Neural/glial Astrocytic hamartoma
Massive (pseudoneoplastic) retinal gliosis
Hematological Primary intraocular (vitreoretinal) lymphoma
Metastases Retinal metastases from systemic lymphoma
Retinal metastases from solid tumor (melanoma, lung adenocarcinoma,
and others)
RPE Congenital hypertrophy of the RPE (CHRPE)
Simple hamartoma of the RPE
Adenoma of the RPE
Adenocarcinoma of the RPE
Combined Combined hamartoma of the RPE and retina
a
Retinal vascular tumors of prenatal origin (retinal cavernous hemangioma and retinal arteriovenous communications)
maintain retinal tight junctions and hence do not manifest retinal leakage (subretinal fluid or hard exudates). In contrast,
vascular tumors of postnatal origin (retinal capillary hemangioma and retinal vasoproliferative tumor) are without reti-
nal tight junctions and hence manifest retinal leakage (subretinal fluid or hard exudates)
b
Recently published clinical histopathologic, immunohistochemical, and molecular findings indicate predominance of
astrocytes rather than vascular components within these tumors. Hence, reactive retinal astrocytic tumor has been pro-
posed as an alternate terminology to describe these retinal tumors rather than labeling them as a vasoproliferative tumor
p rognostication and to scrutinize our treatment retina and RPE. The reader is invited to develop
modalities – past and future. For the first time diagnostic algorithms based on our suggested
for any cancer, the TNM classification for reti- framework (Table 1.1).
noblastoma includes heredity (H) and hence has
evolved to TNMH.
In this chapter, we classify the lesions a clini- Tumors of the Retina
cian encounters while examining a patient with a
retinal or retinal pigment epithelium lesion. Retinal tumors can be benign or malignant and can
Therefore, this is an overview rather than an occur across the age spectrum. The most fre-
exhaustive list of the possible. Included are quently encountered intraocular tumor in children
lesions that do not fit into a single neat box, such is retinoblastoma. If treated inadequately, it is
as combined hamartoma of the retina and the reti- fatal. The cell of origin is controversial but is
nal pigment epithelium (RPE). There are some thought to be a photoreceptor progenitor cell [3].
tumors that have only been described in a handful Its benign variant is retinoma or retinocytoma.
of case reports and are not included in the general Simulating lesions in children include Coats’ dis-
classification, as taxonomy cannot give weight to ease, an idiopathic exudative retinopathy [4], per-
incidence of a disease. We also exclude lesions of sistent primary hyperplastic vitreous, and Toxocara
the RPE and retina that do not resemble a tumor retinitis. Vascular lesions include the capillary and
such as reactive pigmentation of the RPE. cavernous hemangiomas of the retina and the rac-
Due to the complexity of classifying the spe- emose hemangioma, which is really an arteriove-
cific lesions, we classified the tumors for the easi- nous malformation [5]. A reactive tumor of adults,
est reference, clinically by site, divided into the which can mimic the retinal capillary hemangi-
1 Classification of Retinal and Retinal Pigment Epithelium Tumors 3
oma, is the vasoproliferative tumor – a lesion that examination. Ultrasonographic examination, opti-
is benign and in the spectrum of Coats’ disease [6]. cal coherence tomography, and angiography all
Recent histopathologic, immunohistochemical, have a role to play in this process. The retina and
and molecular findings indicate predominance of retinal pigment epithelium can form several dif-
astrocytes rather than vascular components within ferent tumor types, and a classification allows the
these tumors and hence the notion that an alterna- ophthalmologist, pathologist, and oncologist to
tive term for the vasoproliferative tumor is reactive communicate with each other and colleagues. The
retinal astrocytic tumor [7, 8]. TNM eighth edition has an ocular oncology sec-
Some retinal tumors are associated with sys- tion to facilitate this in regard to malignant tumors.
temic disease, such as the retinal capillary hemangi- Over the next chapters, these tumor types are dis-
oma (von Hippel-Lindau syndrome), the astrocytic cussed in detail. As new knowledge becomes
hamartoma (tuberous sclerosis complex and neuro- available in terms of genetics and molecular
fibromatosis), and the combined retinal and retinal workup, classifications will continue to evolve.
pigment epithelial hamartoma (neurofibromatosis
type 2). Massive retinal gliosis can mimic a retinal
tumor [9]. Hematological malignancy can manifest References
in the eye as primary intraocular lymphoma, which
is now described as vitreoretinal lymphoma as it 1. Berman JJ. Tumor classification: molecular analysis
meets Aristotle. BMC Cancer. 2004;4:10.
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ity, mimicking uveitis [10]. Secondary tumors to Retinoblastoma. In: Amin MB, Edge SB, Greene FL,
the retina are possible, though true retinal metasta- editors. AJCC Cancer Staging Manual. New York:
ses are extremely rare. Springer; 2017.
3. Eagle RC Jr. The pathology of ocular cancer. Eye
(Lond). 2013;27(2):128–36.
4. Shields JA, Shields CL. Review: coats disease: the 2001
umors of the Retinal Pigment
T LuEsther T. Mertz lecture. Retina. 2002;22(1):80–91.
Epithelium 5. Knutsson KA, De Benedetto U, Querques G, et al.
Primitive retinal vascular abnormalities: tumors and
telangiectasias. Ophthalmologica. 2012;228(2):67–77.
Neoplasia of the retinal pigment epithelium is rare. 6. Shields CL, Shields JA, Barrett J, et al. Vasoproliferative
Adenocarcinomas, and indeed their benign vari- tumors of the ocular fundus. Classification and clini-
ants, adenomas, are reported [11]. Hamartomas cal manifestations in 103 patients. Arch Ophthalmol.
1995;113(5):615–23.
of the retinal pigment epithelium can be simple, 7. Poole Perry LJ, Jakobiec FA, Zakka FR, et al. Reactive
involving only this cell type, or can be combined retinal astrocytic tumors (so-called vasoprolifera-
with retinal dysplasia [12]. Congenital hypertro- tive tumors): histopathologic, immunohistochemical,
phy (CHRPE) of the retinal pigment epithelium and genetic studies of four cases. Am J Ophthalmol.
2013;155(3):593–608. e1
is very frequently encountered but only rarely 8. Singh AD, Soto H, Bellerive C, et al. Reactive reti-
spawns an adenoma or adenocarcinoma. Atypical nal astrocytic tumor (focal nodular gliosis): report of
CHRPE lesions are associated with familial ade- the clinical Spectrum of 3 cases. Ocul Oncol Pathol.
nomatous polyposis. 2017;3(3):235–9.
9. Yanoff M, Zimmerman LE, Davis RL. Massive gliosis
of the retina. Int Ophthalmol Clin. 1971;11(3):211–29.
10. Coupland SE, Damato B. Lymphomas involving the
Conclusion eye and the ocular adnexa. Curr Opin Ophthalmol.
2006;17(6):523–31.
11. Shields JA, Shields CL, Gunduz K, et al. Neoplasms
When faced with a patient with an intraocular of the retinal pigment epithelium: the 1998 Albert
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tern recognition leads to a differential diagnosis. Ophthalmol. 1999;117(5):601–8.
Parameters such as age and ethnicity narrow pos- 12. Shields CL, Shields JA, Marr BP, et al. Congenital
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Coats’ Disease
2
Thomas M. Aaberg Jr. and Liliya Shevchenko
Introduction Etiology and Pathogenesis
In 1908, George Coats, curator of the Royal London Histologic preparations of eyes affected by
Ophthalmic Hospital, described an ophthalmic Coats’ disease reveal irregular dilation, thicken-
disease which was typically unilateral, had a pre- ing and hyalinization of retinal vessels (capillar-
dilection for healthy males, and resulted in focal ies, arteries, and veins), attenuation of endothelial
deposition of exudates within the fundus and “pecu- cells, and disorganized and necrotic vessel walls
liar” retinal vascular findings [1]. Four years later, [1, 4–7]. Large aneurysms (50–350 μm), seen
Coats classified his cases of “exudative retinitis” after trypsin digestion, frequently formed large
into three groups [2]. Group I manifested massive sausage-like or beaded outpouchings [6]. Other
exudation but no discernable vascular abnormalities. findings include PAS-positive deposits in vessel
Group II had marked vascular disease, intraretinal walls and the outer retinal layer, intraretinal and
hemorrhage, and exudation. Group III presented subretinal cysts, hemorrhage, cholesterol, and
with obvious arteriovenous malformations and exu- lymphocytic infiltrates (Fig. 2.1).
dation. Group III was later considered as a retinal Unfortunately, the histologic findings have
hemangioma. During this same time, Theodor Leber not led to the elucidation of the cause of Coats’
described a nonexudative retinal vascular degenera- disease. Polysaccharide deposition in the vessel
tion characterized by “multiple miliary aneurysms” lumen and retinal hypoxia have been suggested
[3]. Leber’s multiple miliary aneurysms are now in the past as pathogenic mechanisms [8, 9].
believed to represent an early stage of Coats’ disease More recently, attention has focused on the role
[3]. In this chapter, we provide a comprehensive of vascular endothelial growth factor (VEGF) as a
review of pathogenesis, clinical findings, treatment potential player in pathogenesis of Coats’ disease.
options, and prognosis of Coats’ disease. Elevated levels of VEGF have been demonstrated
in both aqueous and vitreous humor of affected
T. M. Aaberg Jr. (*) eyes [10, 11]. In their relatively large study, Zhao
Department of Ophthalmology, Retina Specialists of et al. demonstrated increasing VEGF concentra-
Michigan, Michigan State University, Spectrum tion with progressively higher stages of Coats’
Health, Grand Rapids, MI, USA
disease by showing the correlation between the
levels of intraocular VEGF and the extent of
L. Shevchenko
exudative retinal detachment [12]. However, it
Department of Ophthalmology/Vitreoretinal Disease,
Retina Specialists of Michigan, remains unclear whether the increased VEGF was
Grand Rapids, MI, USA the cause or the consequence of Coats’ disease.

6 T. M. Aaberg Jr. and L. Shevchenko
a b
Fig. 2.1 Enucleated eye with Coats’ disease. Note the tion of PAS-positive material in the outer retina.
total exudative retinal detachment (arrow) and the subreti- Cholesterol clefts are seen in the subretinal exudate
nal exudate (asterisk) (a, low-power hematoxylin and (arrowhead) (b, high-power hematoxylin and eosin)
eosin). Cystic degeneration, disorganization, and deposi-
Nitric oxide (NO)—the mediator of vascular dila- Table 2.1 Classification of Coats’ disease
tion and permeability—is also elevated in the Stage Retinal findings
aqueous humor of the eyes affected by Coats’ dis- Stage 1 Retinal telangiectasia only
ease compared to controls [13]. Stage 2 Telangiectasia and exudation
Gene mutations found in conditions associated 2A Extrafoveal
2B Foveal
with Coats’ disease are being researched as well.
2B1 Without subfoveal nodulea
Mutation in CTC1 gene, encoding conserved telo- 2B2 With subfoveal nodulea
mere protein, has been recently attributed to Coats’ Stage 3 Exudative retinal detachment
plus syndrome discussed later within this chapter 3A Subtotal
[14]. A somatic mutation of the NDP gene encod- 1 Extrafoveal
ing norrin, a protein with important role in retinal 2 Foveal
angiogenesis, and the CRB1 (crumbs homologue 3B Total retinal detachment
Stage 4 Total retinal detachment and glaucoma
1) gene has also been implicated in Coats’ disease
Stage 5 Advanced end-stage detachment
[15, 16]. Unfortunately, it is unclear if the Coats’-
Based on data from Ref. [17]
like changes are secondary events or due to an a
Proposed new subcategories within stage 2B by Daruich
independent genetic mutation. et al. [26]
Clinical Features there are reports of cases presenting within the

first month of life and as late as the eighth decade
The most common presenting signs in an affected of life [17–20].
child are strabismus and leukocoria. About 25% Clinical findings vary in Coats’ disease
of cases are detected by screening eye examina- depending on the five different stages of the dis-
tion. There is a gender predilection for Coats’ ease (Table 2.1) [21]. Early in the disease process,
disease, affecting males eight times more than vascular telangiectasia occurs focally within the
females. And while the majority of cases are uni- retina, most often near or anterior to the equator
lateral, bilateral disease has been reported in up with predilection for temporal and inferior quad-
to 10% of cases [17]. The majority of cases pres- rants (Fig. 2.2) [17, 22]. Vitreoretinal traction is
ent before the second decade of life; however, usually absent. The macula is involved in only 1%
2 Coats’ Disease 7
Fig. 2.2 Fundus photograph of the left eye demonstrates of bulbous aneurysms, vascular telangiectasia, and areas
the circinate lipid exudation surrounding retinal telangiec- of capillary nonperfusion (b)
tasia (a). Fluorescein angiography demonstrates the area
of these early cases [17]. The entire retinal vas- diagnosis, monitor progression, and guide treat-
culature (arteries, veins, and capillaries) appears ment of this condition.
to be affected. The caliber of the involved vessels Fluorescein angiography is helpful both for
varies as aneurysmal dilation and progressive tel- diagnostic purposes, to assess the extent of the
angiectasia occur. The aneurysms may be saccular disease and guide ablative therapy. Angiographic
(sausage shaped) or bulbous (often described as evaluation is particularly helpful in cases where
having a “light-bulb” appearance). As the disease the retinal telangiectasia is subtle or obscured by
progresses, nearly all cases will develop intrareti- lipid exudation. Typical fluorescein angiographic
nal exudation and exudative retinal detachment. findings include retinal telangiectasia, patchy areas
Intraretinal and subretinal exudates often migrate of capillary dropout, and characteristic “light-bulb”
toward the macula. Macular fibrosis is reported to vascular aneurysm (Fig. 2.2). Areas of capillary
occur in 23% and is hypothesized to be a result of dropout are replaced with arteriovenous shunts.
intraretinal neovascularization [23]. Intraretinal Fluorescein leaks from these incompetent vessels,
macrocysts develop in 10% of cases, most likely resulting in cystoid macular changes or large areas
due to coalescence of microcystic spaces in of intra- and subretinal fluorescein collections.
chronically detached and edematous retina [17, Optical coherence tomography is helpful in
24]. Hemorrhagic macrocysts have been reported assessing the extent and staging of central retinal
[25]. The anterior segment changes such as iris involvement including the presence of sub- and
neovascularization, secondary glaucoma, corneal intraretinal fluid and exudates, intraretinal edema,
edema, suspension of lipid and protein in the the size of lipid deposits, ellipsoid zone disruption,
aqueous humor, and cataract do not occur until external limiting membrane disruption, subretinal
late in the disease process [21, 22]. fibrosis, and subfoveal nodule formation [27].
Gupta and colleagues report that microstructural
abnormalities on OCT are predictive of baseline
Diagnostic Evaluation visual acuity and visual prognosis [28].
In recent years, new imaging modalities have
In most cases, Coats’ disease can be diagnosed become valuable in the evaluation and manage-
by clinical examination. However, various imag- ment of Coats’ disease. Ultra-widefield (UWF)
ing modalities are implemented to confirm the images are arguably able to identify more retinal
pathology than standard fundus photography, even In more advanced cases of Coats’s disease, a
in clinically unaffected fellow eyes. In one study, total or near total exudative detachment exists.
UWF angiography detected pathology in seven Clinical or angiographic examination of the reti-
out of nine (78%) of clinically unaffected eyes nal vasculature may be difficult if not impossible.
[29]. Optical coherence tomography angiography In such cases, imaging with ocular ultrasonogra-
(OCT-A) has shown limited usefulness. OCT-A is phy, computerized tomography (CT), or magnetic
accurate in identifying type 3 neovascularization in resonance imaging (MRI) may be necessary. The
Coats’ disease by showing coarse vessels in foveal characteristic ultrasonographic findings include
avascular zone (FAZ) suggesting vascularized a relatively immobile, thickened, detached retina
fibrosis [29]. This is a useful test since indocyanine with homogeneous subretinal fluid and medium
green (ICG) angiography is not routinely used in reflective echogenic clefts (Fig. 2.4). Highly
imaging Coats’ disease. Abnormal FAZ structure reflective foci representing calcium deposition,
with inner retinal vessels traversing the avascular frequently associated with retinoblastoma, are
zone in the superficial capillary plexus in both clin- rarely seen in Coats’ disease. When present in
ically affected and unaffected eyes has also been Coats’ disease, it usually represents osseous
observed [30]. Stanga et al. noted a significant metaplasia of the retinal pigment epithelium in
increase in the foveal vessel density of the super- end-stage, phthisical eyes.
ficial capillary plexus on OCT-A in unaffected fel- Computerized tomography can also detect
low eyes [31]. Therefore, due to newer imaging calcium deposition, thereby facilitating differen-
modalities, what was always believed to be mostly
unilateral disease is now being viewed as a highly
asymmetric bilateral condition (Fig. 2.3). a
b
b
Fig. 2.4 Diagnostic ultrasonography of the eye in

Fig. 2.1. Note the diffuse, homogeneous medium reflec-
tivity of the posterior segment on B scan (asterisk). The
Fig. 2.3 UFW photograph of the right eye in a 66-year- numerous echogenic clefts represent cholesterol crystals
old male with Coats’ disease showing multiple saccular within the subretinal exudates (a). These crystals account
aneurysms, retinal telangiectasia, vascular sheathing, and for the medium reflective spikes seen on the A scan
lipid exudation in the periphery (a) and macula (b) (bracket, b)
tiation of retinoblastoma from Coats’ disease. CT sex predilection, bilateral involvement, more
has a sensitivity of 96% in detecting calcification severe progression, inferior and temporal retinal
in retinoblastoma, while MRI sensitivity is 91.7% involvement, and diffuse pigment alteration in
[32]. Even though MRI cannot image bone or both eyes. Development of Coats’-like retinitis
calcium, making this imaging mode somewhat pigmentosa is strongly associated with mutations
suboptimal, recent concerns over cumulative bio- in crumbs homologue 1 gene (CRB1) [38].
logic effects of radiation may sway physicians to Cataract formation, a common and a relatively
elect MRI [33]. MRI does have superior soft tis- benign condition in adults, is a frequent feature in
sue contrast resolution. On T1-weighted images, pediatric population with Coats’ disease and can
the subretinal space is hyperintense. T2-weighted aggravate visual prognosis. Total white cataracts
images can be either hyper- or hypointense and posterior subcapsular cataracts were found to
depending on the extent of the retinal detachment be the most prevalent type in Coats’ disease [39].
and composition of the exudate. While the retina
normally enhances following gadolinium con-
trast infusion, there is no significant enhancement Systemic
of the subretinal fluid associated with Coats’ dis-
ease; this is in contrast to retinoblastoma, which The most common association is with muscular
shows post-gadolinium enhancement [33, 34]. dystrophy [40]. In a study of 64 patients affected
Fine needle aspiration of the subretinal exu- with facioscapulohumeral muscular dystrophy,
date demonstrates cholesterol crystals, lipid- and 48 (75%) had angiographic findings of retinal tel-
pigment-laden macrophages, and the absence of angiectasia [40, 41]. Concurrent CNS finding has
tumor cells [35]. Fine needle aspiration biopsy, also been reported, including central nervous sys-
while useful, should not be used routinely. Since tem venous malformations [42] and cerebral cal-
retinoblastoma is a possible diagnosis, fine nee- cifications [43]. Beyond these cases, there exist
dle aspiration biopsy runs the risk of seeding the only case reports of Coats’ disease associated
orbit with viable retinoblastoma cells. In non- with a variety of syndromes such as dystonia with
seeing eyes with total retinal detachments and an PANK2 mutation [44], Turner’s syndrome [45],
uncertain diagnosis, enucleation should be pre- Cornelia de Lange syndrome [46], Hallermann-
ferred over the fine needle aspiration biopsy. Streiff syndrome [47], Osler-Weber-Rendu dis-
ease [9], and Revesz syndrome [14, 48].
Coats’ plus disease, also known as cerebro-
Associations retinal microangiopathy with calcifications and
cysts (CRMCC), is a pleiotropic telomeric short-
Ophthalmic and systemic associations have been ening disorder characterized by bilateral retinal
reported with cases of Coats’ disease and should telangiectasias, exudative retinopathy, intracra-
be suspected particularly in cases diagnosed with nial calcifications, bone marrow abnormalities,
bilateral involvement. and gastrointestinal vascular ectasias [14]. It is an
autosomal recessive disorder caused by homozy-
gous or compound heterozygous mutations in the
Ophthalmic CTC1 gene on chromosome 17p13.1, which is
responsible for telomere replication. CTC1 gene
Bilateral retinal exudation, retinal telangiec- is expressed in endothelial cells, and disease fea-
tasia, and even angioma can occur in patients tures are thought to result from small vessel vas-
with Coats’-like retinitis pigmentosa (Fig. 2.5) culopathy with retinal features similar to Coats’
[36, 37]. Coats’-like retinitis pigmentosa is an disease [49]. Retinal vascular abnormalities are
atypical form of RP. Coats’-like changes occur often the presenting feature; therefore, an exam-
in as many as 1.2–3.6% of patients with retini- iner has to be aware of this condition in order to
tis pigmentosa [36]. It can be differentiated from coordinate prompt systemic management and
classic Coats’ disease by older age of onset, no genetic counseling.
a b
c d
Fig. 2.5 Retinal telangiectasia, exudative retinal detach- retinal telangiectasia (a, b). There was cystoid macular
ment, and retinitis pigmentosa. A 12-year-old male pre- edema in both eyes. The optic discs had overlying gliotic
sented with night blindness and constricted visual fields in tufts. Additionally, mottled granularity of the retinal pig-
both eyes. Family history includes an older sister with ment epithelium (RPE) was noted in the mid-periphery of
retinitis pigmentosa. Visual acuities were 20/40 in both both retinas (a, b). A fluorescein angiogram confirmed
eyes. Anterior segment examination was normal. The pos- retinal telangiectasia and macular edema (c). He under-
terior segment of the right eye showed subretinal exuda- went successful treatment with cryotherapy (c) and laser
tion in the superotemporal and inferotemporal quadrants, photocoagulation (d). Genetic testing revealed heterozy-
with associated serous retinal detachment, and overlying gous mutation in CRB1 gene
Differential Diagnosis presents at an earlier age and is more often

bilateral (40% of cases), and 10% have a fam-
The diagnosis of early-stage Coats’ disease is ily history. Retinoblastoma tumors are white to
often straightforward. Foremost in the differen- flesh colored in contrast to the yellow coloration
tial diagnosis of later stages is retinoblastoma, of lipid seen in Coats’ disease. Retinoblastoma
thereby making the stakes of an accurate diag- tumors have an intrinsic vascular supply and
nosis high (Table 2.2). Similar to Coats’ dis- often have associated calcium deposits. Small-
ease, retinoblastoma most often presents with and even medium-sized tumors do not typically
leukocoria and strabismus [50]. Exudative have associated lipid exudation, though serous
retinal detachments may be present in either retinal detachments will occur in exophytic
condition. However, retinoblastoma typically tumors.
Table 2.2 Coats’ disease and retinoblastoma

Coats’ disease Retinoblastoma
Demographics Mean age at diagnosis 5 years 1.5 years
Male 76% 50%
Family history 0% 10%
Ophthalmic findings Unilateral 95% 60%
Retinal vessels Irregular dilatation with Regular dilatation and
telangiectasia tortuosity
Retinal mass Absent Present
Retinal exudation Present Absent
Vitreous seeds Absent Present
Diagnostic imaging USG Retinal detachment Retinal detachment with
calcification
CT scan Calcification absent Calcification present
MRI Retinal detachment Retinal detachment with
enhancing mass
Abbreviations: USG ultrasonography, CT computerized tomography, MRI magnetic resonance imaging
Based on data from Ref. [50]
Vitreoretinal traction rarely occurs in Coats’ Incontinentia pigmenti will have typical derma-
disease. In contrast, vitreoretinal traction fre- tologic and dental findings characteristic of the
quently occurs in many childhood vitreoreti- disease.
nopathies which are associated with retinal Retinal capillary hemangioma may most
telangiectasia, such as familial exudative vitreo- closely resemble Coats’ disease. These cases
retinopathy (FEVR), retinopathy of prematurity, have dilated tortuous arteries and veins, vascu-
persistent hyperplastic primary vitreous, incon- lar shunts, and lipid exudation. Features, which
tinentia pigmenti, Norrie’s disease, and retinal differentiate these vascular tumors from Coats’
capillary hemangioma (Table 2.3). For example, disease, are the dilated tortuous feeding arteri-
FEVR is a bilateral autosomal dominantly inher- oles and draining veins, the focal nodularity of
ited vitreoretinal disease. These patients develop the tumor, and lack of telangiectasia.
peripheral retinal telangiectasia and neovascular- Retinal arterial macroaneurysms can occur in
ization, which may be associated with lipid exu- patients with uveitis due to sarcoidosis in up to
dation, shunt vessel formation, and aneurysmal 17% of cases. Some authors have even suggested
dilations much like Coats’ disease. However, for patients with macroaneurysms and choroiditis
another manifestation of FEVR is abnormal vit- to be evaluated for sarcoidosis [51].
reoretinal adhesions resulting in retinal traction.
When significant traction occurs, a falciform fold
may develop from the disc to the involved periph- Treatment
eral retina, or the retina may tractionally detach.
Retinopathy of prematurity (ROP), another bilat- The natural history of Coats’ disease is usually
eral vitreoretinal disease, will have a history of of a progressive disease. Though the rate of
premature birth and a demarcation separating progression is variable, the majority of affected
vascularized and avascular retina. Persistent eyes will develop severe vision loss. Between
hyperplastic primary vitreous (PHPV) is a con- 64 and 80% of eyes will become phthisical and
genital, typically unilateral, malformation. The develop advanced glaucoma or retinal detach-
eyes are small, and the anterior chamber is often ment [20]. Management of Coats’ disease
shallow. Echography can often elucidate a stalk varies according to the stage of disease. Only
emanating from the disc or another posterior rarely will the telangiectasia regress spontane-
pole location and extending to the lens capsule. ously [52].
Table 2.3 Differential diagnosis of exudative retinopathy

Demographics Ophthalmoscopic findings Systemic
Sex
Entity Age (%) Laterality Exudation Traction Other Inheritance Features
Coats’ 5 years M (75) Unilateral + − Telangiectasia Sporadic Absent
disease (95%)
FEVR 0–3 months M (50) Bilateral + + Peripheral retinal AD Absent
F (50) avascular zone AR
XR
Sporadic
Retinopathy Premature M (50) Bilateral − + Neovascularization Sporadic Complications
of neonate F (50) Vitreous of premature
prematurity hemorrhage birth
PHPV 0–5 years M (50) Unilateral − + Microphthalmia Sporadic Absent
F (50) Cataract
Shallow AC
Vitreous stalk
Incontinentia 0–16 years F (100) Bilateral + + Optic atrophy XD Skin rash
pigmenti Foveal Hypodontia
hypoplasia
Dystrophic
nails
Norrie’s At birth M (50) Bilateral + + Retrolental mass XR Cognitive
disease F (50) Sporadic Behavioral
Hearing loss
Retinal 25 years M (50) Unilateral + − Capillary AD VHL disease
capillary F (50) or bilateral hemangioma Sporadic
hemangioma
Abbreviations: M males, F females, AC anterior chamber, FEVR familial exudative vitreoretinopathy, VHL von Hippel-
Lindau, PHPV persistent hyperplastic primary vitreous, AD autosomal dominant, AR autosomal recessive, XR X-linked
recessive, XD X-linked dominant, + present, – absent
formed in cases of absent or minimal exudative

Observation retinal detachment, favorable structural response
after green laser treatment has been observed in
Observation can be considered in some cases advanced Coats’ disease (stage 3) when treat-
with early telangiectasia (stage 1) or telangiec- ment was directed at vascular abnormalities [53].
tasias with exudation (stage 2) that is not vision
threatening. Advanced non-seeing but comfort-
able eyes can be monitored as well. Cryotherapy
Cases with a shallow exudative retinal detach-

Laser Photocoagulation ment can be successfully treated with a double
freeze-thaw cryotherapy (Figs. 2.5d and 2.6).
The treatment should be initiated once progres- Multiple treatment sessions every 3 months are
sion is documented and exudation becomes usually necessary with either laser or cryotherapy.
significant. The first line of treatment is laser pho-
tocoagulation and/or cryotherapy (Fig. 2.5c, d).
The goal is to ablate the nonperfused retina and Intravitreal Therapy
areas of telangiectasia. The entire area of retinal
telangiectasia needs to be treated. Even though Successful use of anti-VEGF therapy in con-
laser photocoagulation works best when per- junction with ablative therapy (cryotherapy
a b
c d
Fig. 2.6 A 20-month-old child with leukocoria OS. Note year later, there is marked reduction in the macular exuda-
prominent exudation in the macular region (a) and retinal tion accompanied by fibroglial and pigment proliferation
telangiectasia in the inferotemporal quadrant (b). He was at the foveola (c). Note chorioretinal atrophy with second-
treated with multiple sessions of laser photocoagulation ary pigment proliferation at the treatment site (d)
and cryotherapy to the involved regions of the retina. One
or panretinal laser photocoagulation) has Intravitreal corticosteroid injection may play a

been reported [54–56]. Anti-VEGF therapy role in treatment of Coats’ disease by suppressing
has been shown to decrease macular edema inflammation, attenuating leukostasis, and decreas-
and exudates and even reverse tractional ing vascular permeability. Intravitreal triamcino-
retinal detachment (TRD). However, Li and lone injection followed by ablative therapy has been
colleagues summarized multiple reports of successful in treatment of exudative retinal detach-
patients with late- and early-stage Coats’ dis- ment [58]. This adjunct to ablative therapy has to be
ease in whom the use of intravitreal bevaci- weighted against adverse effects of corticosteroids
zumab or ranibizumab was associated with such as cataract formation and steroid response
development of vitreoretinal fibrosis and TRD glaucoma. Dexamethasone implant, with its safer
[57]. Additional research is warranted to fur- profile, can serve as a good alternative to intravitreal
ther elucidate the role of anti-VEGF therapy triamcinolone. There are several reports on success-
in Coats’ disease. ful use of dexamethasone implants for treatment
Fig. 2.7 OCT of the right macula in a 25-year-old male location (a). Patient underwent intravitreal dexametha-
depicting macular edema due to Coats’ disease. Edema sone injection and showed resolution of macular edema at
was not amenable to focal laser treatment due to central 6-week follow-up (b)
of vasoproliferative tumors associated with Coats’ sively detached, surgical drainage of the sub-
disease [59]. The authors of this chapter have had retinal exudate can be considered. This is
good success treating Coats’-associated macular accomplished with a sclerotomy in the area of
edema with an intravitreal dexamethasone implant greatest exudation. Often, more than one scle-
(Fig 2.7a, b) rotomy is required. If a significant amount of
exudate must be drained, balanced saline solu-
tion is infused via either an anterior chamber or
Surgical Drainage a posterior chamber infusion cannula. A poste-
rior chamber infusion cannula should only be
In advanced cases of Coats’ disease where placed if it can be safely passed through the pars
vision is still preserved but the retina is exten- plana without damaging the lens or retina and
extends far enough that the tip does not end in learning of Braille alphabet may have to be
the subretinal space. Once the subretinal exu- recommended.
date is drained, laser photocoagulation or cryo-
therapy is performed. Transscleral drainage
accompanied by intravitreal injection of anti- Follow-Up
VEGF and laser photocoagulation has shown
great success in management of advanced Disease recurrence in 7–10% of eyes up to a
Coats’ disease (stage 3) with exudative retinal decade from initial treatment has been reported
detachment [60]. Li and his colleagues hypoth- [17, 21, 22]. Consequently, a lifetime of follow-
esize that the success and benefit of external up is necessary. Once stable, a patient should be
drainage come from clearing the toxic milieu seen every 6–12 months. Setting realistic expec-
in which the photoreceptors are bathed and tations and providing a general timeline for fol-
eliminating proinflammatory cytokines and low-up care are essential.
profibrotic signals, such as VEGF [57]. Some
surgeons elect to encircle the eye with a scleral
buckle to minimize tractional forces generated Prognosis
at the vitreous base.
Overall, it can be expected that roughly 75%
of patients will have an anatomic improvement
Vitreoretinal Techniques or stabilization of the affected eye with treat-
ment [21]. The remaining 25% will worsen or
Although ablative therapy is the mainstay for require enucleation. As expected, patients with
initial treatment for Coats’ disease regardless of early-stage disease fare far better than those
the stage, there are instances when a drainage with more advanced stages. In a series of 124
procedure with or without vitrectomy is war- eyes (117 patients), 73% of patients with tel-
ranted, particularly in instances of severe exuda- angiectasia with or without extrafoveal lipid
tive retinal detachment or tractional detachment exudate had better than 20/200 vision, whereas
due to retinal surface membrane proliferation only 26% of patients with partial or total exu-
[61, 62]. The argument for early vitrectomy dative retinal detachments attained this level
comes from the theory that it may prevent TRD of vision [21]. The natural progression in
by clearing profibrotic signals from the vitreous advanced Coats’ disease is toward the develop-
cavity as well as removing vitreous collagen ment of a blind, painful eye or to a phthisical
which serves as a scaffold for TRD’s formation state [63].
[57]. Despite those benefits, vitrectomy is still
not advised as a first-line therapy for stage 3B
disease. Conclusion
A definitive therapy for Coats’ disease will

Supportive Care largely depend on a better understanding of
its pathogenesis. Without an adequate animal
Protective eyewear must be stressed. These model or an implicated gene, future develop-
are often healthy active young boys poten- ments will be hindered. Associations with
tially predisposed to incurring injuries. Every other disease entities such as muscular dystro-
effort should be made to prevent injury to phy will hopefully lead to the etiologic gene. In
the unaffected eye, without deterring normal the meantime, our treatment of Coats’ disease
daily or sporting activities. For bilateral cases, will need to concentrate on early detection and
visual rehabilitation with low vision aids and modulation of the affected retina via retinal
ablation (laser and cryotherapy) or pharmaco- 17. Shields JA, Shields CL, Honavar SG, et al. Clinical
variations and complications of Coats disease in 150
logic stabilization of exuding vessels. cases: the 2000 Sanford Gifford Memorial Lecture.
Am J Ophthalmol. 2001;131(5):561–71.
18. Smithen LM, Brown GC, Brucker AJ, et al. Coats’
disease diagnosed in adulthood. Ophthalmology.
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Cerebroretinal microangiopathy with calcifications
Retinal Vascular Tumors
3
Sachin M. Salvi, Paul A. Rundle, Ian Rennie,
and Arun D. Singh
Retinal vascular tumors represent at least four retinal vascular tumors are summarized in
distinct clinical entities which include retinal Table 3.1 and further discussed under neuro-
capillary hemangiomas, retinal cavernous hem- oculo-cutaneous syndromes (phakomatoses)
angiomas, retinal arteriovenous communications (Chap. 9).
(Wyburn-Mason syndrome), and retinal vasopro-
liferative tumor. Retinal vascular tumors can also
be considered as congenital or prenatal in origin, Retinal Capillary Hemangioma
maintaining retinal tight junctions and hence not
manifesting retinal leakage, such as subretinal Introduction
fluid or hard exudates (retinal cavernous heman-
gioma and retinal arteriovenous communications Although these retinal vascular tumors have been
[Wyburn-Mason syndrome]), or acquired/postna- characterized as hemangioblastomas, various
tal in origin without retinal tight junctions and authors have recommended that the term capil-
hence manifesting retinal leakage, such as sub- lary hemangioma rather than hemangioblastoma
retinal fluid or hard exudates (retinal capillary or hemangioendothelioma be used to describe
hemangioma and retinal vasoproliferative tumor/ these vascular tumors [1]. Retinal capillary hem-
reactive retinal astrocytic tumor). Each of the angiomas can be further classified on the basis of
subtypes has characteristic clinical features, and their location within the retina (peripheral and
an attempt should be made to differentiate them juxtapapillary), morphology (endophytic, exo-
because of specific systemic associations, treat- phytic, and sessile), effects on the retina (exuda-
ment, and prognosis associated with them. The tive form and tractional form), and their
clinical features and systemic associations of relationship to von Hippel-Lindau (VHL) disease
(with or without VHL disease).
S. M. Salvi (*) · P. A. Rundle · I. Rennie Clinical Features

Sheffield Ocular Oncology Service, Royal
Retinal capillary hemangiomas are multiple in
about one-third of patients, and up to half the
A. D. Singh
cases have bilateral involvement. The mean age
Department of Ophthalmic Oncology,
Cole Eye Institute, Cleveland Clinic, at diagnosis of retinal capillary hemangioma in
Cleveland, OH, USA VHL disease is approximately 25 years [2].

20 S. M. Salvi et al.
Table 3.1 Diagnostic features of various retinal vascular tumors

Feeder Systemic
Type Appearance Location vessels Exudation association
Capillary hemangioma Round red mass Juxtapapillary/ Prominent Present VHL disease
peripheral
Cavernous Grape-like clusters Nonspecific Absent Absent CNS hemangioma
hemangioma
Arteriovenous Dilated/tortuous Near the disc Absent Absent Wyburn-Mason
malformations retinal vessels syndrome
Vasoproliferative Globular pale mass Periphery Absent Present Absent
tumor
VHL von Hippel-Lindau disease
Symptoms planning. OCT evaluation of these lesions

Patients typically notice progressive worsening shows a hyper-reflective lesion with little inner
of vision which may be associated with photop- tumor detail, but macular evaluation by OCT is
sias. Many patients are asymptomatic and are useful for detecting associated macular edema,
detected on a routine examination or on screen- epiretinal membranes, and subretinal fluid
ing evaluation because of the family history of (Fig. 3.2). OCT-A appears to be promising non-
VHL disease [3]. invasive imaging tool in the diagnosis and moni-
toring of posterior non-leaking retinal capillary
Signs hemangiomas [6]. Compared to fluorescein
Ophthalmoscopically a retinal capillary heman- angiography, OCT-A is able to identify tiny
gioma appears as a circumscribed, round retinal tumors, but only those closer to the posterior
lesion with an orange-red color with prominent pole. Both FA and OCT-A could identify the
feeder vessels (Fig. 3.1). Intraretinal and subreti- intrinsic vasculature and feeder vessel in juxta-
nal exudation is often seen around the tumor or in papillary tumors and small tumors not identified
the macula. The majority of retinal capillary on ophthalmoscopic examination. However, the
hemangiomas are located in the superotemporal tumors and their feeding and draining vessel
and inferotemporal peripheral retina [4]. were better defined by OCT-A than by
Prominent retinal vessels emerging from the FA. OCT-A failed to image the peripheral
optic disc are highly suggestive of a peripherally tumors [6].
located retinal capillary hemangioma. In con-
trast, juxtapapillary retinal capillary hemangio-
mas are not associated with visible prominent
feeder vessels. Box 3.1 Salient Diagnostic Findings
Diagnostic Evaluation • Single or multiple, circumscribed,

orange-red-colored round retinal lesion
The fundus findings of retinal capillary heman- • Retinal exudation and/or subretinal fluid
giomas are characteristic, and the diagnosis can surrounding the lesion which may
usually be made based solely on ophthalmo- extend into the macular region
scopic examination. Fluorescein angiography is • Prominent feeder vessels extending
the most informative diagnostic tool because of from the optic disc (absent in juxtapapil-
the vascular nature of the tumor (Fig. 3.1) [5]. lary variant).
Fluorescein angiography also helps in differen- • Prominent and early filling on fluores-
tiating the feeder arteriole from the draining cein angiography with late leakage
vein and is therefore important for treatment
3 Retinal Vascular Tumors 21
a b
c d
e f
Fig. 3.1 Fundus photograph of a retinal capillary heman- photodynamic therapy, increased gliosis hemorrhage (d).
gioma. Note prominent feeder vessels and retinal exuda- Six months after the treatment, there is complete resolu-
tion (a). The hemangioma has a rim of gliosis and tion ofmacular exudates and reduction in size of the feeder
surrounding and subretinal fluid and hemorrhage (b). vessels (e). The lesion has regressed with increased gliosis
Fluorescein angiography identifies the feeder artery (c). and total resolution of surrounding and subretinal fluid
Marked hyperfluorescence and leakage are characteristic and hemorrhage (f)
findings. One week after treatment with standard fluence
Fig. 3.2 Retinal a
capillary hemangioma.
Clinical appearance (a).
OCT evaluation shows a
round hyper-reflective
lesion with little inner
tumor details (b)
Differential Diagnosis examination reveals that the macroaneurysm is

centered on the retinal arteriole.
Some of the conditions that should be consid- Important findings that differentiate a retinal
ered in the differential diagnosis include Coats’ capillary hemangioma from a vasoproliferative
disease, macroaneurysm, and other forms of reti- tumor are the absence of prominent feeder ves-
nal vascular tumors [7]. Coats’ disease is an sels in a vasoproliferative tumor and its extreme
idiopathic unilateral retinal vascular disease of peripheral location in the inferior retina [10].
young males which is characterized by retinal Retinal capillary hemangioma is more commonly
telangiectasia and retinal exudation [8]. The seen in the temporal quadrants of the midperiph-
younger age of onset, unilateral involvement, eral retina [7]. Unlike retinal capillary hemangi-
predilection for males, and lack of systemic fea- oma, vasoproliferative tumors are non-familial
tures are helpful differentiating features. and lack significant systemic association [10].
Moreover, Coats’ disease has prominent areas of
retinal telangiectasia rather than distinct retinal
vascular tumors. reatment of Retinal Capillary
T
Retinal macroaneurysm has many features Hemangioma
that differentiate it from retinal capillary heman-
gioma [9]. In general, macroaneurysm is seen as There are several methods of treating a retinal
a single lesion in the posterior pole in older indi- capillary hemangioma, and the choice of treat-
viduals and is more likely to present with subreti- ment is determined by the size, location, and
nal, intraretinal, or vitreous hemorrhage rather associated findings of subretinal fluid, retinal
than retinal exudation. Most importantly, the traction, and the visual potential of the eye [11].
feeder vessels are absent, and careful fundus The treatment can be challenging due to the
p resence of multiple tumors in both eyes and the lary retinal capillary hemangioma as they tend to
potential for the onset of new tumors. remain stable [12].
Observation Laser Photocoagulation

Careful observation in a reliable patient can be Laser photocoagulation applied over many ses-
recommended if the retinal capillary hemangi- sions is effective (91–100%) in treating retinal
oma is very small (up to 500 microns), is not capillary hemangiomas that are up to 4.5 mm in
associated with exudation or subretinal fluid, and size, but is most effective in tumors that are
is not visually threatening [11]. Initial observa- 1.5 mm or smaller in size (Fig. 3.3) [13].
tion should always be considered in juxtapapil- Photocoagulation can be applied directly to the
a b
c d
Fig. 3.3 Small retinal capillary hemangioma observed on tocoagulation (c). Four weeks later, the hemangioma is
surveillance examination in a patient with VHL disease partially regressed and surrounded by a chorioretinal scar
(a). The hemangioma could be visualized with fluorescein (d). (Reprinted from Singh and Schachat [65]. With per-
angiography (b). Appearance immediately after laser pho- mission from Elsevier)
tumor or to the feeder artery, or a combination of Photodynamic Therapy

both techniques can be used [14]. More recently, photodynamic therapy has been
reported to induce occlusion of peripheral
Cryotherapy (Fig. 3.1) and juxtapapillary retinal capillary
Cryotherapy is preferable to photocoagulation hemangioma (Fig. 3.5) [12, 16, 17, 18].
when the retinal capillary hemangioma is located
anteriorly and the retinal capillary hemangioma Radiotherapy
is more than 3.0 mm in diameter (Fig. 3.4) [15]. Retinal capillary hemangiomas that are greater
Cryotherapy may also be preferred when there is than 4 mm show a poor response to cryotherapy
moderate amount of subretinal fluid. The efficacy and laser photocoagulation, and such tumors can
of cryotherapy is greater with smaller tumors be treated successfully with plaque radiotherapy
(less than 1.5 mm) [11]. [19]. Low-dose external beam radiotherapy is also
a b
c d
Fig. 3.4 Cryotherapy for retinal capillary hemangioma. reduction in macular exudation (d). The macular appear-
Macular exudation (a) and peripheral solitary retinal cap- ance continues to improve with slow resolution of
illary hemangioma (b). Note reduction in tumor vascular- exudation (e, 6 months) without additional intervention
ity and surrounding reactive pigment proliferation (f, 12 months). Cryotherapy also led to partial peeling of
3 months after double freeze-thaw cryotherapy (c) and the epiretinal membrane (final visual acuity 20/20)
e f
Fig. 3.4 (continued)
Fig. 3.5 Initial fundoscopic photograph (a) and OCT (b, photodynamic therapy in same patient, which reveals sta-
fovea) of the left eye of 27-year-old female (patient 1) bilization of tumor with decreased edema. (Reprinted
with juxtapapillary retinal capillary hemangioma and from Sachdeva et al. [16]. With permission from John
associated cystoid macular edema. Fundoscopic photo- Wiley & Sons)
graph (c) and OCT (d) approximately 2 years following
an option in cases that do not respond to the usual Cavernous Hemangioma

methods of treatment listed above [20]. Low-dose of the Retina
proton beam therapy (22 Gy) can provide satis-
factory anatomical outcome in severely advanced Introduction
juxtapapillary capillary hemangiomas [21].
Cavernous hemangiomas of the retina are com-
Anti-VEGF Therapy posed of multiple, thin-walled dilated vascular
Although anti-VEGF therapy is extensively used channels with surface gliosis [25]. The walls are
in a variety of retinal vascular conditions, its use lined by non-fenestrated endothelium, explaining
in the treatment of retinal capillary hemangioma the lack of exudation [26]. Two forms of cavern-
remains unproven with variable response in ous hemangioma of the retina are recognized:
lesion size and exudation [22, 23]. sporadic and syndromic [25]. It has been sug-
gested that the cerebral cavernous malformation
Vitreoretinal Procedures syndromes should be included with the neuro-
Pars plana vitrectomy, retinal detachment repair, oculo-cutaneous (phakomatoses) syndromes, but
and other related procedures are usually required the association of cerebral and cutaneous heman-
for larger retinal capillary hemangiomas that are giomas is inconsistent [25].
complicated by rhegmatogenous or tractional
retinal detachments.
Clinical Features
ssociation with Von Hippel-Lindau

A Cavernous hemangiomas of the retina are believed
Disease to be a rare form of congenital hamartoma with a
recent literature review identifying only 96 cases
Retinal capillary hemangiomas can occur spo- [27]. The age of presentation in a series of nine
radically or in association with VHL disease [7, patients ranged from 1 to 55 years [28].
24]. The association of retinal capillary heman-
gioma with VHL disease is discussed in detail Symptoms
under neuro-oculo-cutaneous syndromes (phako- Patients with cavernous hemangioma of the ret-
matoses) (Chap. 9). ina may be asymptomatic or may present with
reduced vision from a macular location of the
hemangioma, macular fibrosis, or vitreous hem-
Prognosis orrhage. Recent OCT studies have revealed OCT
an overlying epiretinal membrane forming
The visual prognosis, even in adequately treated bridges between the saccules, contraction of
cases, is guarded [7]. Overall more than 25% of which could exert traction and cause vitreous
affected patients show permanent visual loss, and hemorrhage (Fig. 3.6) [29].
about 20% have vision of less than 20/100 in at
least one eye [4]. However, the visual outcome is Signs
greatly dependent on the size, location, and num- Retinal lesions appear as grape-like clusters of
ber of retinal capillary hemangiomas and the blood-filled saccular spaces in the inner layers of
presence of exudative or tractional retinal detach- the retina or on the surface of the optic disc
ment. As retinal capillary hemangiomas progres- (Fig. 3.6) [25]. The size and location of the heman-
sively enlarge, the visual outcome is much better gioma are variable but most are solitary small (1–2
in cases that are diagnosed and treated before the disc diameters) lesions involving the m idperipheral
onset of symptoms [4]. or peripheral retina [24]. Epiretinal membranes are
a b
d
c
Fig. 3.6 Fundus photograph of a papillary cavernous attached to the saccules and forming bridges between
hemangioma of the retina (a). Note the absence of retinal them (b). Peripheral variant may not be prominent (c). On
exudation. Optical coherence tomography of the retinal fluorescein angiogram characteristic hyperfluorescent
cavernous hemangioma. An overlying epiretinal mem- saccular dilatations are evident (d)
brane is imaged as a continuous hyper-reflective signal
usually present. There are no prominent feeder diagnostic test in establishing the correct diagno-
vessels, and there is a lack of subretinal or intra- sis. It demonstrates retinal origin of the heman-
retinal exudation. Rarely, cavernous hemangiomas gioma with a low-flow system and hence delayed
may be multiple and extensive involving 360° of filling in the venous phase (Fig. 3.6). The saccu-
the midperipheral retina [30]. lar dilatations in the hemangioma appear as fluo-
rescent caps due to staining of supernatant plasma
overlying collections of sedimented erythrocytes.
Diagnostic Evaluation Although cavernous hemangiomas are distrib-
uted randomly in the fundus, they tend to follow
The ophthalmoscopic findings of cavernous hem- the course of a major vein; however feeder ves-
angiomas of the retina are characteristic. sels are not prominent. There is characteristic
Fluorescein angiography is the most helpful absence of leakage.
OCT reveals a disorganized epiretinal mem- therapy may be useful in symptomatic peripheral
brane with cystic spaces within inner and outer retinal cavernous hemangiomas [33].
retinal layers, these spaces representing the sac-
cular aneurysms [31]. OCT-A reveals rarefaction
of retinal vessels overlying the tumor and the Association with CNS Hemangioma
absence of a flow signal at the superficial and
deep plexi [32]. Cavernous hemangiomas of the retina may be
associated with cerebral cavernous malforma-
tions in the context of an autosomal dominant
Box 3.2 Salient Diagnostic Findings syndrome with high penetrance and variable
expressivity [34–36]. The association between
retinal and CNS hemangiomas is discussed in
• Retinal lesions appear as grape-like detail under neuro-oculo-cutaneous syndromes
clusters of blood-filled saccular spaces (phakomatoses) (Chap. 9).
in the inner layers of the retina or on the
surface of the optic disc.
• Overlying epiretinal membranes are Prognosis
usually present.
• Absence of prominent feeder vessels. The vast majority of cases of cavernous heman-
• Lack of subretinal fluid and intraretinal gioma of the retina remain asymptomatic, do not
exudation. progress, and require no treatment. A small num-
• May be associated with CNS ber of cases may have an associated self-limiting
hemangioma. vitreous hemorrhage. With time, cavernous hem-
angiomas of the retina undergo progressive
thrombosis and often demonstrate an increase in
surface gliosis. In contrast, cerebral cavernous
Differential Diagnosis hemangiomas may have serious consequences
such as seizures, intracranial hemorrhages, and
Cavernous hemangiomas of the retina should be even death [34].
differentiated from other vascular disorders such
as Coats’ disease, retinal capillary hemangiomas,
retinal arteriovenous communications, and reti- Wyburn-Mason Syndrome
nal vasoproliferative tumors. The presence of
dilated feeder vessels and retinal exudation does Introduction
not support the diagnosis of retinal cavernous
hemangioma. Wyburn-Mason syndrome is a rare sporadic dis-
order characterized by congenital arteriovenous
malformations principally of the retina and brain.
reatment of Retinal Cavernous
T Other involved tissues may include the skin,
Hemangioma bones, kidneys, muscles, and gastrointestinal
tract [37, 38].
In general, cavernous hemangiomas of the retina
are nonprogressive, may undergo spontaneous
thrombosis, and rarely cause vitreous hemor- Clinical Features
rhage. No treatment is necessary in asymptom-
atic cases. Argon laser photocoagulation or Although usually congenital in origin, the diag-
cryotherapy can be attempted but does not elimi- nosis of retinal arteriovenous malformations is
nate the likelihood of relapse [25]. Proton beam most commonly made later in childhood.
a b
Fig. 3.7 Fundus appearance of a typical retinal arteriovenous malformation (a). On fluorescein angiography arteries
and veins appear undistinguishable (b)
Symptoms Fluorescein angiography is the most helpful

Patients with retinal arteriovenous malformations diagnostic test in establishing the correct diag-
may be asymptomatic. These lesions are often nosis. It demonstrates abnormal arteriovenous
detected as an incidental finding in an asymptom- connections and presence or absence of inter-
atic patient or as a cause of visual impairment in vening capillaries. In the most severe cases
an “amblyopic” eye. (Grade III), arteries and veins cannot be differ-
entiated even on angiography (Fig. 3.7).
Signs Abnormal retinal vasculature characteristically
Arteriovenous malformations are seen readily on demonstrates absence of leakage. On OCT,
ophthalmoscopic evaluation. These malforma- dilated intraretinal vascular channels are
tions have been classified into three groups observed (Fig. 3.8).
depending upon the severity of vascular malfor-
mation [39]. Those in group I have an abnormal
capillary plexus between the major vessels of the
arteriovenous malformations. Group II arteriove-
nous malformations lack any intervening capil- Box 3.3 Salient Diagnostic Findings
lary between the artery and vein. Group III
arteriovenous malformations are the most exten-
sive with dilated and tortuous vessels and no • Retinal arteriovenous malformations
apparent distinction between the artery and vein appear as abnormally dilated and tortu-
(Fig. 3.7). ous retinal vessels.
• Absence of prominent feeder vessels.
• Lack of subretinal fluid and intraretinal
Diagnostic Evaluation exudation.
• May be associated with intracranial
The ophthalmoscopic findings of arteriovenous arteriovenous malformations.
malformations of the retina are characteristic.
Fig. 3.8 Wyburn- a
Mason syndrome.
Clinical appearance of a
typical lesion consisting
of markedly dilated and
tortuous vessels (a). On
OCT, dilated intraretinal
vascular channels are
observed (b)
Differential Diagnosis Prognosis
Retinal arteriovenous communications should be The retinal vascular anomalies may alter in con-
differentiated from other vascular disorders listed figuration over many years exhibiting increasing
above. The presence of dilated feeder vessels and tortuosity [40] and sometimes leading to vascular
retinal exudation goes against the diagnosis of occlusions [41] and retinal ischemia with devel-
retinal arteriovenous communications. opment of neovascular glaucoma. Patients with
Group III retinal arteriovenous malformations
have a high risk of visual loss either as a result of
reatment of Retinal Arteriovenous
T retinal decompensation or via direct compression
Communications of retinal nerve fibers or optic nerve [42, 43].
The retinal vascular malformations are usually

not amenable to any therapy. Retinal Vasoproliferative Tumor
Introduction
Association with Intracranial
Arteriovenous Malformations Retinal vasoproliferative tumors are uncommon
retinal lesions which have only been recognized as
The exact incidence of intracranial arteriovenous a distinct clinical entity since 1982 when Baines
malformations in patients with retinal arteriove- reported the combination of a peripheral telangiec-
nous malformations is not known. This topic is tatic nodules and posterior fibro-cellular mem-
discussed in detail elsewhere. branes in five patients [44]. These lesions were
initially termed as “presumed acquired retinal may be evident especially in secondary tumors
hemangiomas” to differentiate them from capil- [10]. Macular fibrosis (31%) and edema (18%)
lary hemangiomas [45]. The nomenclature has may lead to visual loss.
varied in the literature, but at present vasoprolif-
erative retinal tumors are the widely accepted ter-
minology [10]. Histologically these lesions are Diagnostic Evaluation
composed of a mixture of glial cells, retinal pig-
ment epithelial cells, and a network of fine capil- Ancillary investigations such as fluorescein angi-
laries with some larger dilated blood vessels [46, ography are of limited value because of the
47]. The clinical and histopathologic features of peripheral nature of most lesions. In cases where
vasoproliferative tumor seem to overlap with angiography is possible, the lesions typically fill
recently described reactive retinal astrocytic tumor rapidly in the early phase with increasingly
that can be observed in response to a degenerative, hyperfluorescence and diffuse leakage in the late
inflammatory, or ischemic retinal insult [48–50]. phases (Fig. 3.9). Telangiectatic and dilated ves-
sels are frequently observed within the tumor
mass. Ultrasonography confirms a raised solid
Clinical Features lesion with high internal reflectivity on both A-
and B-scans. Intraocular biopsy may be neces-
Vasoproliferative retinal tumor usually presents sary to establish a diagnosis in difficult cases
in the third or fourth decade, and both sexes are [52]. The peripheral tumor location makes it dif-
equally affected [10]. The majority of patients ficult to image with OCT. Vision loss is usually
with primary tumors are solitary (87%) in con- due to epiretinal membrane or exudative macular
trast to those with secondary tumors where mul- detachment, and OCT is useful to identify these
tiple lesions were found in 42% of cases. changes.
Symptoms
Reduced vision, photopsia, and metamorphopsia
are common presenting symptoms. Some asymp- Box 3.4 Salient Diagnostic Findings
tomatic cases are diagnosed incidentally on an
ophthalmoscopic evaluation.
• Vasoproliferative tumor appears as a
Signs globular yellowish-pink vascular mass.
Vasoproliferative tumor appears as a globular • Inferior peripheral retinal location.
yellowish-pink vascular mass in the peripheral • Absence of dilated, tortuous, feeder
retina (Fig. 3.9). These lesions lack the dilated, vessels.
tortuous, feeder vessels typically seen in retinal • Associated retinal exudation, subretinal
capillary hemangioma, but retinal vessels of nor- fluid, and macular fibrosis.
mal or near-normal caliber may be seen entering • Pre-existing ocular disease such as
the lesion posteriorly [51]. Vasoproliferative reti- intermediate uveitis, other inflamma-
nal tumors have a predilection for the inferotem- tion, or retinitis pigmentosa.
poral retina. Subretinal exudation, which may be
extensive, is common occurring in over 80% of
cases [10]. Exudative retinal detachment, retinal
and vitreous hemorrhage, and vitreous, epiretinal Differential Diagnosis
membrane cells are frequent associated findings
(Fig. 3.10). Retinal pigment epithelial hyperpla- Atypical lesions may be confused with adult Coats’
sia adjacent to the vasoproliferative retinal tumors disease, retinal capillary hemangioma, eccentric
a b
c d
Fig. 3.9 Fundus appearance of a retinal vasoproliferative the late phase of the fluorescein angiogram (c) and sec-
tumor. Note prominent retinal lipid exudation and bullous ondary epiretinal membrane (d). Six weeks after cryo-
exudative retinal detachment (a). The vasoproliferative therapy, there is resolution of lipid exudation, bullous
tumor appears as a globular yellowish-pink vascular mass exudative retinal detachment, (e) and resolution of the
in the peripheral retina (b). Diffuse hyperfluorescence in peripheral tumor (f)
a b
c d
Fig. 3.10 Fundus appearance of a retinal vasoprolifera- in secondary epiretinal membrane (b) with onset retinal
tive tumor. Note prominent retinal lipid exudation and neovascularization (c) necessitating intravitreal injection
peripheral hemorrhagic tumor (a). Following treatment of bevacizumab (1.25 mg. 0.05 ml). Four weeks later, the
with plaque radiation therapy (35 Gy), there was increase tumor appeared totally avascular and gliotic (d)
choroidal neovascularization (disciform), or even hemangiomas are subretinal and are rarely sur-
amelanotic melanoma. Adult Coats’ disease is uni- rounded by any significant degree of exudates.
lateral and usually in males. There is extensive lipid B-scan ultrasonography can help differentiate from
exudation and macular edema. The presence of amelanotic melanoma as VPT are solid lesions and
retinal telangiectasia and areas of capillary nonper- without choroidal excavation.
fusion with adjacent webs of filigree-like capillar-
ies helps differentiate adult Coats’ from a VPT
[53].The absence of distinct feeder vessels or fam- Treatment of Vasoproliferative
ily history is of value in differentiating a vasoprolif- Tumors
erative retinal tumor from a retinal capillary
hemangioma. Careful examination of the tumor’s Observation
vascular supply should confirm their retinal origin Small peripheral vasoproliferative retinal tumors,
in contrast to an eccentric disciform which arises lacking significant exudate or maculopathy, can
beneath the sensory retina. Similarly, choroidal be managed by periodic observation. If the lesion
is symptomatic or associated with a significant Intravitreal Anti-VEGF Therapy

amount of exudate or detachment, then treatment and Dexamethasone Implants
is warranted. Intravitreal injections with anti-VEGF agents or
dexamethasone implants are showing promising
Cryotherapy results though it is unclear if the results will be
Vasoproliferative retinal tumors can be treated maintained in the long term. These agents may be
successfully with triple freeze-thaw transcon- used in isolation or as an adjunct to cryotherapy
junctival cryotherapy, although repeat treatments (Figs. 3.10 and 3.11) [60, 61] or PDT to prevent
may be required (Fig. 3.9) [10]. However, a large macular edema and diminish tumor vascular
tumor may require heavy cryotherapy which in leakage [62].
turn can result in significant complications, and
such tumors are probably best managed by other
treatment modalities. Association with Vasoproliferative
Tumors
Plaque Brachytherapy
Large lesions can be managed effectively using About 25% of all vasoproliferative tumors are
either ruthenium or iodine plaque brachytherapy secondary to a pre-existing congenital, inflam-
(Fig. 3.10) [10, 54–56]. matory, vascular, traumatic, dystrophic, and
degenerative ocular disease such as intermediate
Photothrombotic and Photodynamic uveitis, retinitis pigmentosa, and ocular toxoplas-
Therapy mosis [10]. Rare occurrence in monozygotic
Indocyanine green-mediated photothrombotic twins [63], Waardenburg syndrome [64], neurofi-
therapy [57] and photodynamic therapy have bromatosis 1 [61], and possible association with
been shown to be effective in the treatment of systemic hypertension and hyperlipidemia has
vasoproliferative tumors [58, 59]. been reported (Fig. 3.11) [10].
a b
Fig. 3.11 Slit lamp photograph of the right eye at presen- therapy and two intravitreal injections of bevacizumab,
tation demonstrating multiple Lisch nodules and florid the neovascularization of the iris resolved almost com-
neovascularization of the iris (a). On gonioscopic exami- pletely (c). The vasoproliferative tumor appeared less vas-
nation there was 360° neovascularization of the angle. In cular with chorioretinal atrophy and hyperpigmentation of
the inferior fundus, there was a pink, elevated vascular the posterior margin (d). Note resolution of lipid exudates.
mass with surrounding lipid exudate, consistent with (Reprinted from Hood et al. [61]. With permission from
vasoproliferative tumor (b). After treatment with cryo- Slack Incorporated)
c d
Prognosis capillary hemangioblastoma. Indian J Ophthalmol.

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In a large series of 103 patients, up to one-third of disease. Surv Ophthalmol. 2001;46(2):117–42.
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However, even small peripherally located vasop- sive exudation. Roy Lond Ophthalmol Hosp Rep.
1908;17:440–525.
roliferative tumors may be associated with a sig- 9. Rabb MF, Gagliano DA, Teske MP. Retinal arterial mac-
nificant loss of vision. Advanced cases can roaneurysms. Surv Ophthalmol. 1988;33(2):73–96.
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Retinal Astrocytic Tumors
4
Christopher Seungkyu Lee, Sungchul Lee,
and Arun D. Singh
Introduction where no lesion was earlier present (Fig. 4.1).

Later in life, they may assume a more densely
Retinal astrocytic tumors are benign glial tumors white color and develop multinodular mulberry-
represented by two clinical types: retinal astro- looking calcification.
cytic hamartoma and “acquired” retinal astro-
cytoma. Retinal astrocytic hamartomas are
frequently associated with tuberous sclerosis Pathogenesis and Pathology
complex (TSC). “Acquired” retinal astrocytomas
develop in somewhat older individuals who have It is postulated that astrocytic hamartomas in
no clinical manifestations of TSC or other sys- TSC arise from undifferentiated glioneurocytes
temic syndromes. during the embryonal development of the retina
[3]. Genetic analysis has identified two distinct
variants of TSC, which result from mutations in
Retinal Astrocytic Hamartoma TSC1 gene on chromosome 9q34 and the TSC2
gene on chromosome 16p13 [4, 5]. TSC1 and
Astrocytic hamartoma of the retina and optic TSC2 are tumor-suppressor genes, and their gene
nerve head typically occurs in patients with TSC products, hamartin and tuberin, respectively,
(Bourneville’s disease), but it may also rarely be form a protein complex and act together to inhibit
found in patients with neurofibromatosis (von mammalian target of rapamycin (mTOR)-medi-
Recklinghausen’s disease), retinitis pigmentosa, ated signaling [6]. Clinical manifestations of
or as an isolated finding [1, 2]. In younger indi- TSC are more frequent and severe in patients
viduals, the semitranslucent tumors may arise with TSC2 mutations than TSC1 mutations [7–9].
As such, TSC2 mutations are more frequent in
patients with retinal astrocytic hamartoma than in
C. S. Lee · S. Lee (*) those without tumor [10].
Department of Ophthalmology, Severance Hospital, Histopathologically, astrocytic hamartomas
Yonsei University, College of Medicine, are typically composed of elongated fibrous
Seoul, South Korea
astrocytes that have small oval nuclei and inter-
lacing cytoplasmic processes. Others may be
A. D. Singh
composed of large pleomorphic astrocytic cells.
Cole Eye Institute, Cleveland Clinic, Some tumors may exhibit histopathological
Cleveland, OH, USA similarities to Müller cells, suggesting a

40 C. S. Lee et al.
Fig. 4.1 Fundus appearance of a 10-year-old Asian girl a new flat, smooth, semitranslucent lesion (white
with tuberous sclerosis complex. Note retinal astrocytic arrow), which was not evident previously became
hamartoma adjacent to optic nerve head with central noticeable (b)
calcification resembling mulberries (a). After 6 months,
p ossible Mülller cell origin [11]. Blood vessels

and areas of calcification, often in the form of Diagnostic Evaluation
calcospherites, can be present. Mitotic figures
are extremely rare. In the majority of cases, diagnosis of retinal
astrocytic hamartoma can be made with indirect
ophthalmoscopy and a search for various mani-
Clinical Features festations of TSC, including the classic triad of
seizures, mental deficiency, and adenoma seba-
Symptoms ceum (facial angiofibroma) (Chap. 9). However,
Patients are often visually asymptomatic and fluorescein angiography, fundus autofluores-
tumors are detected as part of screening for cence, ultrasonography, and optical coherence
TSC. Visual symptoms could be caused by macu- tomography (OCT) can be useful ancillary stud-
lar involvement, tumor growth, vitreous hemor- ies, especially in subtle lesions (Box 4.1).
rhage, vitreous seeding and vitritis, or intraretinal
and subretinal exudation [12–15].
Box 4.1 Salient Diagnostic Findings
Signs
Although tumors exhibit considerable variation
from case to case, three basic types have been • Single or multiple, circumscribed, semi-
recognized based on ophthalmoscopic appear- translucent round retinal lesion
ance: (1) relatively flat, smooth, noncalcified, • Single or multiple, large, elevated, nod-
and semitranslucent lesions; (2) large, elevated, ular, and calcified mulberry lesion
nodular, calcified lesions resembling mulberries; • Absent or minimal retinal exudation or
and (3) a mixed type of lesion-possessing fea- subretinal fluid surrounding the lesion
tures of (1) and (2), being calcified in the central • Absence of prominent feeder vessels
portion and semitranslucent in the periphery extending from the optic disc
[16–19] (Fig. 4.2a). The first type is the most • Prominent network of fine retinal ves-
common, followed by the second and third. All sels on fluorescein angiography
three morphological types may be seen in a • Lack of growth over short periods of
given patient. observation (weeks to months)
4 Retinal Astrocytic Tumors 41
a b
c d
Fig. 4.2 Fundus appearance of a typical retinal astrocytic rior shadowing. Note the “moth-eaten” empty spaces that
hamartoma. Note central area of calcification and periph- may represent intralesional calcification (c). Fundus auto-
eral semitranslucent noncalcified region (a). Late-phase fluorescence imaging (confocal scanning laser ophthal-
fluorescein angiogram, showing relatively intense hyper- moscope, Heidelberg Retina Angiograph, Heidelberg
fluorescence of the lesion due to leakage of dye from the Engineering, Heidelberg, Germany) showing strong auto-
tumor vessels (b). Spectral-domain optical coherence fluorescence of the central calcified multinodular part of
tomography imaging of the retinal astrocytic hamartoma the tumor with reduced autofluorescence of the peripheral
showing thickening of retinal nerve fiber layer with poste- semitranslucent rim (d)
Fluorescein angiography of retinal astrocytic background physiologic autofluorescence. Smaller

hamartoma shows a prominent superficial net- lesions may not show hypoautofluorescence and
work of fine vessels in the arterial phase with elude detection, possibly due to insufficient mass
leakage in the venous phase (Fig. 4.2b). Late effect to block the background autofluorescence.
angiograms show intense diffuse homogenous Calcified type 2 tumors are highly autofluorescent.
staining of the mass. Type 3 tumors show increased autofluorescence of
Fundus autofluorescence imaging can aid visu- the central calcified portion of the tumor and
alization of tumors. Type 1 tumors show reduced reduced autofluorescence of the peripheral semi-
autofluorescence, resulting from absence of auto- translucent rim, resulting in a contrast between the
fluorescence from the tumor and its blockade of two tumor compartments (Fig. 4.2c) [20].
42 C. S. Lee et al.
Fig. 4.3 Fundus appearance of calcified large astrocytic tion (b). (Reprinted from Giles et al. [12]. With permis-
hamartoma. Note surrounding retinal exudation (a). sion from Springer Nature)
B-scan ultrasonography indicative of intrinsic calcifica-
Ultrasonography is not generally useful for mass with internal “moth-eaten” optically empty
small, noncalcified type 1 tumors. However, due spaces representing intratumoral calcification,
to calcification within the mass, larger calcified and (4) elevated dome-shaped mass with opti-
lesions can show characteristic features, includ- cally empty intratumoral cavity.
ing acoustic shadowing, on B-scan ultrasonogra-
phy (Fig. 4.3). A-scan ultrasonography shows a
sharp anterior border, high internal reflectivity, Differential Diagnosis
and attenuation of orbital echoes posterior to the
tumor. Despite the characteristic features listed above,
Spectral-domain (SD) OCT offers superior certain entities can closely resemble astrocytic
resolution and enhanced tissue penetration in hamartoma. Retinoblastoma, retinocytoma,
visualizing the retinal location of the tumor and myelinated nerve fibers, massive gliosis of the
ascertain the reason for visual loss. Tumors appear retina, retinal capillary hemangioma, and optic
to be localized within retinal nerve fiber layer disc drusen can be difficult to differentiate oph-
on SD-OCT, often compressing the underlying thalmoscopically from astrocytic hamartoma
inner retinal layer [21]. Large calcified tumors (Table 4.1).
often show multifocal, round, confluent “moth- Small retinoblastomas can have a similar
eaten” empty spaces with posterior shadowing, translucent appearance as astrocytic hamartomas,
which may represent calcification foci or intra- and both lack calcification when small. When
tumoral cavities (Fig. 4.2d) [21–24]. As SD-OCT calcification is present, it can demonstrate subtle
can show more detail on intrinsic tumor features, differences, as it tends to be dull and chalky white
an OCT classification has been proposed to fur- in a retinoblastoma. The calcification in an astro-
ther categorized tumors into four types [22] (1) a cytic hamartoma is more of a glistening yellow,
circular or oval-shaped nonpigmented flat mass resembling fish eggs. In addition, dilated, tortu-
within retinal nerve fiber layer with the intact ous retinal feeder vessels are more common in
underlying the retina, (2) slightly elevated mass retinoblastomas. A larger retinoblastoma often
above the nerve fiber layer with mild inner reti- produces vitreous or subretinal seeding and exu-
nal disorganization and subtle vitreoretinal adhe- dative retinal detachment, which rarely occurs in
sion/traction, (3) a calcified mushroom-shaped astrocytic hamartoma. However, the presence of
Table 4.1 Differential diagnosis of astrocytic hamartoma

Feeder
Diagnosis Appearance Calcification vessels Exudation RPE Growtha Association
Astrocytic Translucent Present; Absent Usually Normal Absent Tuberous
hamartoma or white mass yellow, absent sclerosis
spherical
Retinoblastoma White mass Present; Present Absent Normal Present 13 q deletion
Retinocytoma white, chunky Absent Absent Proliferation Absent syndrome
Myelinated nerve White patch, Absent Vessels Absent Normal Absent None
fibers no mass obscured
Massive gliosis White mass May be Absent May be Atrophy and Absent None
of retina present present proliferation
Retinal capillary Round red Absent Prominent Present Normal May be VHL disease
hemangioma mass present
Optic disc drusen White Present Absent Absent Normal Absent Retinitis
nodular mass pigmentosa
RPE retinal pigment epithelium, VHL von Hippel-Lindau disease
Short-term growth observed over weeks to months
a
a hard exudation supports the diagnosis of astro- a capillary hemangioma is usually red or pink
cytic hamartoma rather than retinoblastoma. (rather than white), has dilated tortuous retinal
Fluorescein angiography may be helpful in cor- feeder vessels, is more likely to produce retinal
rect diagnosis because the blood vessels are of exudation, and is noncalcified.
normal caliber in astrocytic hamartoma, which is The similarity between optic disc drusen and
in contrast to retinoblastoma. In doubtful cases, optic disc astrocytic hamartoma can be so great
close follow-up over several weeks will demon- that the term “giant drusen” has been used to
strate stability in astrocytic hamartoma and describe the calcified astrocytic hamartoma seen
growth in retinoblastoma [18, 25]. with TSC [26]. Although optic disc drusen show
Retinocytoma, a benign counterpart of retino- distinct calcification, they are usually bilateral
blastoma can also closely resemble astrocytic and lie within the disc, whereas the calcified
hamartoma because both lesions may be calci- astrocytic hamartoma is characteristically unilat-
fied. Surrounding retinal pigment epithelial alter- eral, protrudes above the optic disc, and obscures
ations are a common finding in retinocytoma, the disc and retinal blood vessels.
which are typically absent in astrocytic hamar-
toma because it is situated superficially in the
retina. Treatment of Astrocytic Hamartoma
Myelinated nerve fibers sometimes can mimic
a small astrocytic hamartoma. However, myelin- The majority of retinal astrocytic hamartomas are
ated nerve fibers are usually located at or adja- small, extrafoveal, and stationary, so treatment is
cent to the optic disc margin, show a more usually unnecessary. However, periodic ocular
fibrillated margin, are flat without any elevation, examination is warranted, as some tumors may
and are not calcified. demonstrate progressive enlargement, calcifica-
Massive gliosis of the retina can be difficult to tion, and vision-threatening complications,
differentiate clinically from an astrocytic hamar- including vitreous hemorrhage, vitritis and vitre-
toma, but prior history of ocular inflammation or ous seeding, or intraretinal and subretinal exuda-
trauma and a more degenerated eye are important tion (Fig. 4.4).
clues. The exudative complications can be self-
Some astrocytic hamartomas have prominent limited within a few weeks [27]. However, pho-
vascularity, which makes the differentiation from tocoagulation, photodynamic therapy using
retinal capillary hemangioma difficult. However, verteporfin, transpupillary thermotherapy, brachy-
44 C. S. Lee et al.
a b
d
c
f
e
Fig. 4.4 A 14-year-old Asian boy with tuberous sclerosis (c). SD-OCT image across the tumor showed thickening
(TSC1 mutation, exon3–7 deletion) was referred for rou- of retinal nerve fiber layer with posterior shadowing (d).
tine ophthalmologic screening, and no retinal tumor was Two weeks after transpupillary thermotherapy on the
found (a). Just 4 months later, the patient presented with tumor, lipid exudates increased (e), but subretinal fluid
decreased visual acuity (VA) of 20/400. An ill-defined, resolved (f). After multiple sessions of intravitreal bevaci-
semitranslucent yellow-white retinal mass with neovascu- zumab due to vitreous hemorrhage from neovasculariza-
larization and heavy lipid exudates at macula were tion on the tumor, macular lipid exudates regressed and
observed (b). Spectral-domain optical coherence tomog- VA increased to 20/30 with restoration of outer retinal
raphy (SD-OCT) scanned through macular center showed structure on SD-OCT, taken 18 months from the first
detachment of neurosensory retina with subretinal fluid presentation (g)
Fig. 4.5 A 45-year-old Caucasian female with an unre- area. Based on morphological characteristics, the diagno-
markable past medical history was referred for evaluation sis of retinal astrocytoma was made with a decision to
of a peripapillary tumor associated with a scotoma in the observe for progression. At a 6-month visit, VA remained
right eye (a). On initial evaluation, visual acuities (VA) 20/20; however, the lipid exudates were noted to be
were 20/20 in both eyes. An ill-defined, translucent, approaching the foveola (c). Four months after two ses-
yellow-white superficial mass along the superotemporal sions of standard-fluence photodynamic therapy (TAP,
margin of the optic disc and extending into the retina was 1.5-mm spot covering the entire tumor up to the supero-
observed (b). Prominent intrinsic vessels as well as dilated temporal edge of the optic disc), VA remained 20/15, the
collateral vessels were present. The macula was flat; how- lipid exudates were diminished, and some gliosis of the
ever, lipid exudates were present superonasal to the fovea, tumor could be appreciated (d). (Reprinted from Singh
and a few retinal striae were noted in the papillomacular [37]. With permission from Elsevier)
therapy, intravitreal bevacizumab, vitrectomy, or The systemic mTOR inhibitors including siro-
endoresection could be considered in cases with limus and everolimus have been employed to
persistent, progressive, and fovea-involving exu- treat aggressive tumors with some success [40,
dation (Fig. 4.5) [28–36]. 41]. More aggressive cases showing progres-
Vitreous hemorrhage may spontaneously sive growth, tumor seeding, and neovascular
resolve, but persistent or recurrent hemorrhage glaucoma have been managed by enucleation
can be managed with vitrectomy [15, 38, 39]. [42, 43].
46 C. S. Lee et al.
Association with Tuberous Sclerosis ox 4.2 Clinical Features of Retinal

B
Astrocytic Tumors
Retinal astrocytic hamartomas are seen in approx-
imately half of patients with TSC, but variability
in frequency exists with studies reporting ranges • Retinal astrocytic tumors are benign
from 34% to 87% (Chap. 9) [10, 16, 17, 19, 44, tumors representing two clinical types:
45]. When present, retinal astrocytic hamartomas (1) astrocytic hamartoma that is fre-
are bilateral in about half and multiple in about quently associated with tuberous sclero-
one-third to half of patients [10, 16, 19, 44]. Some sis complex and (2) acquired retinal
patients show only a retinal tumor without addi- astrocytoma.
tional findings of TSC. In such cases, which have • Three basic morphological types have
been reported as high as 81% of retinal astrocytic been recognized for astrocytic hamar-
hamartoma [21], the tumor is usually found as a toma: (1) relative flat, semitranslucent,
solitary retinal mass. It is undetermined whether noncalcified lesion; (2) nodular, ele-
it represents a separate entity independent of vated, calcified lesion; and (3) a mixed
TSC, the first clinical manifestation of TSC, or a type of (1) and (2).
forme fruste of TSC. • Tumor occurrence, growth, and calcifi-
In some patients with TSC, retinal achromic cation can be seen during follow-up.
patches have also been observed, with frequen- • Malignant transformation or metastasis
cies ranging from 8% to 39% [19, 46, 47]. They is not known.
can look diffusely hypopigmented or be sur- • In general, visual prognosis is excellent
rounded by some degree of pigment proliferation. and treatment is unnecessary, unless
complicated by vitreous hemorrhage,
exudation, or relentless tumor growth.
Prognosis
Most astrocytic hamartomas remain stable and do

not cause complications. Occasionally, however,
gradual enlargement and calcification of these Acquired Astrocytoma
tumors may be seen, particularly in younger
patients [16]. In rare instances, they can show Retinal astrocytic hamartoma associated with
progressive growth with degenerative necrosis, TSC accounts for the majority of retinal astrocytic
leading to vitreous seeding, vitreous or subreti- tumors. Occasionally, however, an “acquired”
nal hemorrhage, subretinal exudation or detach- astrocytoma can develop at any age, with no fam-
ment, and neovascular glaucoma [14, 32, 36, 42, ily history or association with TSC or other sys-
48, 49]. New lesions may develop from previ- temic syndromes (Fig. 4.6). The exact incidence
ously normal-appearing retina [18]. Spontaneous of this rare tumor is not known, and it has been
regression of retinal astrocytic hamartoma has described in only a few reports [43, 49, 52–54].
been reported [50, 51]. In general, astrocytic An acquired astrocytoma typically begins as a
hamartomas are silent with excellent visual prog- solitary white to fleshy-pink intraretinal mass, usu-
nosis. They are not known to undergo malignant ally in the posterior pole near the optic disc. Acquired
transformation and have no tendency to metasta- retinal astrocytoma seems to have a propensity for
size (Box 4.2). progressive and relentless tumor enlargement, caus-
a b
c d
Fig. 4.6 A solitary multi-lobulated, yellow-white, cir- acteristic of reactive astrocytic glial cells ((b),
cumscribed retinal tumor with fine intrinsic vessels Papanicolaou stain 40x). The astrocytic cells have elon-
located just outside the inferior arcades centered over the gated cytoplasmic processes ((c), Papanicolaou stain
band retinal photocoagulation scars. The tumor was 40x). The cytoplasmic processes stain strongly positive
11 × 7.5 in basal dimensions with height of 2.8 mm. Note with the GFAP immunostain (d). (Reprinted from Singh
surrounding rim of lipid exudation (a). Abundant fibril- et al, [55]. With permission from Karger Publishers ©
lary cytoplasm surrounds relatively uniform nuclei char- 2017 S. Karger AG, Basel)
ing local complications. The true pathogenesis of The best management strategies have not been
acquired retinal astrocytoma is not known. It appar- well established. Radiotherapy may prove use-
ently arises from either typical retinal astrocytes or ful in rare cases where diagnosis is established
Müller cells. The clinical features and pathogenesis by a needle biopsy. In most reported cases, the
of acquired astrocytoma seem to overlap with affected eye has been enucleated because of
recently described reactive retinal astrocytic tumor growth, secondary glaucoma, and/or suspicion
that can be observed in response to a degenerative, that the tumor may be a uveal melanoma or
inflammatory, or ischemic retinal insult [55–57]. retinoblastoma.
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Retinal Pigment Epithelial Tumors
5
Elias I. Traboulsi, Matteo Scaramuzzi,
and Arun D. Singh
Tumors of the retinal pigment epithelium ongenital Hypertrophy of the RPE

C
(RPE) can be congenital or acquired. They may (CHRPE)
also be classified as reactive, hypertrophic,
hamartomatous, or neoplastic (Table 5.1) [1]. Introduction
Those present at birth can be associated with
systemic conditions such as familial adenoma- Congenital hypertrophy of the retinal pigment
tous polyposis (FAP) or neurofibromatosis 2 epithelium (CHRPE) is a round, darkly pig-
(NF2). Acquired RPE tumors include benign mented, flat lesion of the ocular fundus located at
and malignant lesions that are sometimes dif- the level of the retinal pigment epithelium
ficult to differentiate from choroidal neoplasms (Fig. 5.1). In the older literature, CHRPE was
were it not for ancillary tests such as ultraso- classified as a benign melanoma of the retinal
nography, optical coherence tomography, and pigment epithelium [2].
fluorescein angiography. In this chapter we
review the clinical features of congenital and
acquired tumors of the RPE and their systemic Etiology and Pathogenesis
associations.
CHRPE lesions are isolated and sporadic with no
known underlying genetic basis.
E. I. Traboulsi (*)
Department of Pediatric Ophthalmology and Pathology
Strabismus, Center for Genetic Eye Diseases,
Cole Eye Institute (i-32), Cleveland Clinic
Foundation, Cleveland, OH, USA Histopathologically, isolated CHRPE lesions
e-mail: [email protected] consist of a layer of hypertrophied RPE cells
M. Scaramuzzi containing an excessive number of pigment
Department of Pediatric Ophthalmology and granules (Fig. 5.2) [3]. The underlying chorio-
Strabismus, Center for Genetic Eye Diseases, capillaris and choroid are normal. The photore-
Cole Eye Institute, Cleveland Clinic Foundation,
ceptor layer overlying the abnormal RPE may
Cleveland, OH, USA
be normal or may be atrophic, causing a sco-
A. D. Singh
toma. The RPE cells contain granules of pig-
Cole Eye Institute, Cleveland Clinic, ment that resemble melanin in the absence of
Cleveland, OH, USA lipofuscin, suggesting the inability of these RPE

52 E. I. Traboulsi et al.
Table 5.1 Classification of RPE lesions

Type Subtype Variants Other terminology Association
Reactive Hyperplasia Trauma
Metaplasia Inflammation
Toxicity
Hypertrophic Solitary Pigmented Retinal nevus None
Nonpigmented Benign melanoma of
RPE
Grouped Pigmented Bear tracks None
Nonpigmented Polar bear tracks
POFLs* Atypical CHRPE Gardner syndrome Turcot
syndrome
Hamartoma RPE Superficial Congenital None
Full thickness Hamartoma
With intrinsic
vascularization
RPE and retina Combined hamartoma Neurofibromatosis type 2
Neoplastic Adenoma CHRPE (rare)
Adenocarcinoma
Abbreviations: RPE Retinal pigment epithelium, CHRPE Congenital hypertrophy of retinal pigment epithelium, POFLs
Pigmented ocular fundus lesions
*
POFLs can include adenomas of RPE
studied in newborns, documenting the congeni-

tal nature of these lesions and their pigmenta-
tion pattern [5].
Clinical Features
Symptoms
Patients with CHRPE are generally asymptom-
atic unless the macula is involved.
Signs
Ophthalmoscopically, CHRPE patches have
round and sometimes scalloped edges and are
generally located in the fundus periphery. A peri-
Fig. 5.1 Solitary CHRPE. A sharply demarcated pig-
mented flat retinal lesion representing solitary
papillary location is less common. The lesion is
CHRPE. The lighter area represents lacunae which may frequently surrounded by a hypopigmented halo
enlarge slowly over many years and occasionally by a hyperpigmented ring [4].
Punched-out hypopigmented or depigmented
lacunae may be present, and occasionally the
cells to perform their normal phagocytic func- whole patch is depigmented and is referred to as
tion, leading perhaps to the associated photore- an albinotic patch of the peripheral fundus
ceptor degeneration [4]. In the areas that have (Fig. 5.3) [6]. The retina and retinal vessels over-
been termed lacunae, RPE cells have reduced lying the CHRPE appear normal except for occa-
pigmentation or may have dropped out com- sional areas of focal intraretinal pigmentation.
pletely [3]. In these areas glial cells are present Atrophy of the outer and, sometimes, inner reti-
between Bruch’s membrane and the RPE. The nal layers may be present, especially over larger
histopathology of CHRPE lesions has been lesions [4, 7]. Rarely, neovascularization has
5 Retinal Pigment Epithelial Tumors 53
a b
Fig. 5.2 A 62-year-old woman with a large ciliochoroi- showed some loss of nuclear basal polarity and were
dal melanoma (enucleated) and an elliptical retinal pig- packed with variable numbers melanosomes in both api-
ment epithelial lesion about 1 mm temporal to the foveola, cal and basal areas ((b), H&E × 500). Electron micros-
in the horizontal meridian (a). The pathology of the copy showing large but fragmenting melanosomes ((c),
“CHRPE” lesion varied across the lesion, correlating with EM × 32,000). (Reprinted from Parsons et al. [3]. With
the level of pigmentation. Highly pigmented temporal permission from BMJ Publishing Group Ltd)
areas showed RPE hypertrophy. Thickened RPE cells
been noted in association with capillary and large (POFLs) [9]. OCT shows a thickened RPE layer
vessel obliteration [8]. with atrophy of the overlying retina (Fig. 5.3).
Hypertrophied RPE cells block choroidal fluo-
rescence on angiography, and no leakage of
Diagnostic Evaluation dye is observed (Fig. 5.4). The remainder of the
normal-appearing fundus has a normal fluores-
Visual field testing can map the scotoma asso- cein angiographic pattern.
ciated with some CHRPE lesions. The scotoma To the unexperienced observer, CHRPE can
is relative initially but may become absolute if simulate a choroidal melanoma, because
photoreceptor atrophy occurs. ERG and EOG peripheral lesions could appear elevated. In a
studies are normal in patients with CHRPE and review over 330 cases, a correct diagnosis of
in patients with familial adenomatous polyposis CHRPE was made in only 9% of patients, with
and multiple pigmented ocular fundus lesions referring diagnoses of choroidal nevus in 26%,
instance in which neovascularization develops at

a
the edge of the CHRPE lesion [11].
Prognosis
CHRPE is a benign lesion that does not enlarge

significantly except in very rare instances [12].
The significance and pathogenesis of minimal
growth, observed in almost 50% of cases is
unclear [10]. Development of nodules at the edge
of CHRPE lesions, suggestive of RPE adenoma,
has also been observed [11, 13–15].
b
ongenital Grouped Pigmentation
C
of the RPE
Introduction
Multiple areas of circumscribed and flat retinal

pigmentation that are arranged in clusters are
described as congenital grouped pigmentation of
the RPE [16]. The smaller lesions are located
Fig. 5.3 Depigmented CHRPE. Fundus appearance (a). near the apex of the cluster closer to the posterior
OCT reveals thickened retinal pigment epithelial layer
and atrophy of the overlying retinal layers (b) pole [16, 17]. Because of the similarity of the pat-
tern to animal foot prints, they have been referred
to as bear tracks (Fig. 5.4) [16, 18].
choroidal melanoma in 15%, and unspecified
fundus lesions in 48% [10].
Etiology and Pathogenesis
Treatment Meyer et al. have suggested that the growth pat-

tern of grouped CHRPE is similar to cutaneous
The best management is periodic observation. No sectoral pigmentation and speculated that pig-
treatment is necessary except for the very rare mentary mosaicisms may be the manifestation
Fig. 5.4 A 28-year-old asymptomatic Caucasian existing feature was the presence of nonpigmented,
female demonstrated multiple small, flat, dark brown punctate lesions located within the maculae suggestive
to black clusters of retinal pigment epithelium (RPE) of grouped nonpigmented CHRPE. Fluorescein angi-
hypertrophy on dilated fundus examination of the both ography demonstrated persistent hypofluorescence
eyes. These plaque-like lesions were circumferen- correlating with the clinically observed areas of hyper-
tial along the peripheral fundus and were associated pigmentation and hypopigmentation (b). (Reprinted
with smaller foci of pigmentation oriented toward to from Turell et al. [65]. With permission from Taylor
the posterior pole (a). The appearance was consis- & Francis)
tent with grouped pigmented CHRPE. A unique, co-
of a modified wild-type allele in a somatic cell and hypertrophy and hyperplasia are not sig-
clone during early embryogenesis following nificant features [20]. Histopathologic find-
developmental lines analogous to the cutaneous ings in variants of CHRPE are summarized in
lines of Blaschko and that the sectoral distribu- Table 5.2.
tion of grouped pigmentation of RPE may
reflect the stream, outgrowth, and migration of
retinal pigment epithelium cells during embryo- Clinical Features
genesis [19].
In the majority of cases, grouped pigmentation
is unilateral (84%) and is limited to one sec-
Pathology tor of the fundus [17]. In contrast to isolated
patches of CHRPE, there are no depigmented
The histopathology of grouped pigmentation lacunae or overlying photoreceptor abnormali-
of the retina is very similar to that of solitary ties in grouped pigmentation of the retina [18].
CHRPE; however, light and electron micros- However, in rare instances, the lesions can lack
copy have suggested that the pigment granules pigmentation and appear albinotic (polar bear
retain their normal ellipsoid configuration tracks) [1].
Table 5.2 Histopathologic findings in variants of CHRPE

Pigment granules Other findings
Type RPE cells Size Density Shape
Solitary Hypertrophy Large Increased Spherical Thickened Bruch’s membrane
Hyperplasia macromelanosomes Atrophic RPE (lacunae)
Atrophic photoreceptors
Absence of lipofuscin
Grouped Normal Large Increased Ellipsoid Absent RPE hypertrophy Absent RPE
hyperplasia Normal photoreceptors
Atypical Hypertrophy Large Increased Spherical RPE hamartoma
Hyperplasia Abnormal melanogenesis
Abbreviation: RPE retinal pigment epithelium
Diagnostic Evaluation a
The lesions are hypofluorescent on fluorescein

angiography and hypoautofluorescent on fundus
autofluorescence and demonstrate focal outer
retinal atrophy overlying a flat lesion on OCT
(Fig. 5.5) [21].
Treatment
Grouped pigmentation can be just observed as

part of routine ocular examination, no treatment
is needed.
b
Prognosis
Prognosis is excellent. Although congenital

grouped pigmentation of the RPE is not associ-
ated with FAP [16, 22], rare association with
microcephaly has been reported [23].
igmented Ocular Fundus Lesions

P
of Gardner Syndrome
Introduction Fig. 5.5 Pigmented CHRPE. Fundus appearance (a).

OCT reveals atrophy of the overlying retinal layers (b,
Pigmented ocular fundus lesions (POFLs) is a between arrows)
descriptive term that we have used to refer to fun-
dus lesions observed in patients with FAP. It is are not associated with FAP [22]. There are dis-
preferred to use the term POFLs rather than tinct ophthalmoscopic features that distinguish
CHRPE in FAP because the garden variety CHRPE from lesions in FAP, and only some of
CHRPE lesions and grouped pigmentation of the the lesions have histopathologic characteristics
retina and RPE as described above in this chapter compatible with CHRPE (Table 5.3) [24]. POFLs
Table 5.3 Relative differentiating features of CHRPE and POFLs

Feature CHRPE Grouped pigmentation POFLs
Shape Round Variable Oval
Depigmentation Lacunae Absent Tail/lacunae
Size (basal diameter) 0.2–13 mm Variable 0.15–4.5 mm
Laterality Unilateral Unilateral/bilateral Bilateral
Number Solitary or grouped Numerous Four or more
Growth Frequent but Unknown Unknown
minimal
Malignant Rare Never Never
transformation
Histopathology Hypertrophy Hypertrophy Hypertrophy
(RPE changes) Hyperplasia Hyperplasia
Hamartoma
Systemic association None Rare (microcephaly and other Gardner syndrome, Turcot
anomalies) syndrome
Abbreviation: RPE retinal pigment epithelium, CHRPE congenital hypertrophy of retinal pigment epithelium, POFLs
pigmented ocular fundus lesions
have also been referred to as “RPE hamartomas cell layers high composed of hyperplastic RPE
associated with familial adenomatous polyposis” cells; and (4) darkly pigmented lesions that
(RPEH-FAP) [25]. occupy the full thickness of the retina and resem-
ble RPE adenoma (Fig. 5.6). Hence, POFLs in
FAP are probably better considered adenomas or
Etiology and Pathogenesis hamartomas of the RPE.
The presence of multiple POFLs is a highly

specific (>90%) and sensitive (70–80%) marker Clinical Features
for FAP [26]. Several hundred mutations have
been described in the gene for FAP, designated Symptoms
as APC (adenomatous polyposis coli), which Patients with POFL are usually asymptomatic
maps to chromosome 5q21-q22 [27]. Genotype- unless the macula is involved.
phenotype correlation has revealed that POFL
and desmoid tumors are associated with FAP Signs
mutations between codons 311 and 1444 and POFLs are present at birth in about three-quarters
after codon 1444, respectively [28–30]. of patients with FAP. We have observed them in a
preterm infant who was examined in the neonatal
intensive care unit for retinopathy of prematurity
Pathology [32]. They do not seem to increase in size or
number with age, but no such data has been
In addition to the focal hyperpigmented lesions, published.
histopathologic studies have revealed diffuse Ophthalmoscopy underestimates the number of
RPE abnormalities in FAP with hypertrophic lesions because clinicopathologic correlation has
RPE cells that contain lipofuscin granules, multi- revealed that almost three times more lesions were
membranous inclusions, and macromelanosomes present histopathologically than were counted pre-
[31]. POFLs may be divided histopathologically mortem (Fig. 5.6) [31]. We recommend a three-
into four types: (1) lesions consisting of a mono- mirror contact lens exam or pan-retinal photography
layer of hypertrophic RPE cells; (2) lesions to document all lesions. POFLs can take one of a
composed of a small mound of two to three cell number of several configurations. Very small
layers of RPE; (3) thick lesions, seven to eight (<0.1 disc diameter) round dark lesions are usually
a b
c d
Fig. 5.6 POFLs in the right eye of a patient with Gardner a three-mirror contact lens (b). On histopathology, POFL
syndrome (a). Two oval-shaped pigmented retinal lesions may appear as hyperpigmented and hypertrophic RPE (c),
are evident. Note depigmentation along the posterior mar- several layered thick RPE hamartoma (d), and even as
gin (arrow). Numerous peripheral small lesions are easily nodular RPE adenoma (e). (Reprinted from Traboulsi
overlooked unless fundus examination is performed with et al. [31]. With permission from Elsevier)
located in the peripheral fundus in the vicinity of POFLs have a hypopigmented halo and/or poste-
vortex veins, while larger, more characteristic rior depigmented trail. It is often possible to note a
ovoid, tear-shaped, or coffee bean-shaped lesions diffuse fine stippling of RPE pigmentation in the
are located closer to the posterior pole (Fig. 5.6). peripheral fundus. There is a fair degree of intrafa-
Macular lesions have also been observed. Some milial consistency in the number of POFLs.
POFLs can be differentiated from solitary Microcephaly

CHRPE, because they are multiple, bilateral, and CHRPE like lesions have been described in three
usually less defined margins. Unlike congenital siblings (two boys and one girl) with autosomal
grouped pigmentation of the RPE, they are ran- recessive microcephaly and without associated
domly distributed, without a sector preference. systemic features of Gardner syndrome and in
one boy with microcephaly and a chromosomal
Associations abnormality [23, 39].
Familial Adenomatous Polyposis (Gardner

Syndrome) Diagnostic Evaluation
Familial adenomatous polyposis or Gardner
syndrome is a rare autosomal dominant condi- Patients suspected of having FAP need detailed
tion characterized by the development of hun- ocular examination to determine if they show the
dreds of adenomatous colonic polyps [33]. ocular phenotype of the disease. If only one or
Adenocarcinoma of the colon inevitably devel- two lesions are detected on ophthalmoscopy,
ops unless prophylactic colectomy is performed. three-mirror fundus examination or pan-retinal
Many patients develop extracolonic benign photography may be necessary to find additional
lesions such as sebaceous cysts, lipomas, fibro- small lesions. ERG and EOG examinations are
mas, and osteomas. Osteomas are most com- not needed since they are normal. Patients sus-
monly present in the skull and have also been pected of having FAP should be evaluated by gas-
reported in the orbit [34]. POFLs [26] and opaque troenterologists, and the appropriate medical and
jaw lesions [35] are the most common and most surgical interventions should be instituted accord-
characteristic extracolonic manifestations of the ing to current protocols. Prophylactic colectomy
disease. Extracolonic cancers can occur in the is frequently performed in third decade of life
thyroid, adrenal glands, and in the liver [36]. [29]. Mutation analysis of the gene and protein
The presence of four or more POFLs is a truncation assays are available commercially [30].
highly sensitive (70–80%) and specific (>90%)
clinical marker for the FAP [26]. Sensitivity and
specificity is increased slightly if opaque jaw Treatment
lesions are present at the same time [35]. The
presence of POFLs is especially helpful in fami- No treatment is necessary for the POFLs. If
lies where multiple affected individuals have orbital osteoma causes significant ocular prob-
numerous POFLs because of the intrafamilial lems, it may need surgical excision.
consistency of expression of the ocular trait.
Patients at risk for the disease who have the ocu-
lar lesions develop colonic polyps [24]. The Prognosis
absence of POFLs, however, does not rule out the
disease. More recent studies have reported that Prognosis for vision is excellent. Early diagnosis
patients with a mutation APC 1249-1549 develop of FAP results in good prognosis for life if appro-
polyposis at an early age and have a worse sur- priate therapeutic measures are instituted.
vival than patients with a mutation APC 0-178 or
312-412 [37].
Simple Hamartoma of the RPE
Turcot Syndrome
Turcot syndrome is a variant of FAP in which Introduction
patients develop brain tumors. Patients with
Turcot syndrome may also have multiple Simple hamartomas of the RPE are very rare con-
POFLs [38]. genital lesions that were first described by Laqua
in 1981 [20]. The term RPE hamartoma was non-fluorescence on early phases of the fluo-
suggested by Gass [1] who reported three archi- rescein angiogram, with some cases showing
tectural patterns: (1) superficial retinal involve- a central plaque of fluorescence and others
ment, (2) full-thickness retinal involvement and only a ring of fluorescence at the edge of the
preretinal extension, and (3) retinal involvement lesions on late frames. OCT shows abrupt
with intrinsic vascularization. Others have used elevation from the inner retina with posterior
the term congenital hamartoma of the RPE to shadowing [41].
describe these tumors [40].
Treatment
No specific therapy is indicated, and none has
These tumors are congenital, but no specific been tried or deemed necessary as vision is usu-
genetic etiology has been postulated or identified ally well preserved.
in any of the reported cases.
Prognosis
Pathology
There has not been documentation of growth in
Clinicopathologic correlation of simple hamar- any of the reported cases, some of which have
toma of the RPE has not been published. been observed for up to 15 years.
Clinical Features Adenoma and Adenocarcinoma

of the RPE
Symptoms
Patients with simple hamartoma of the RPE are Introduction
generally asymptomatic unless the macula is
involved, in which case there may be loss of These are rare acquired tumors of the RPE. The
vision. differentiation between adenoma and adenocarci-
noma can only be made on the basis of histopath-
Signs ologic findings because of similar clinical
Simple hamartoma of the RPE appears as a dis- findings in both types of tumors.
crete small (0.5–1.0 mm) black nodule and has a
predilection for the macular area. Tumors can be
discovered in children or later in life if vision is Etiology and Pathogenesis
not affected. A feeding arteriole and draining
venule may be apparent ophthalmoscopically or The etiology of RPE adenomas and adenocarci-
observed on fluorescein angiography in all cases. nomas remains elusive, and no genetic factors
Surrounding halo or associated retinal traction is have been identified to date.
present in the majority of patients.
Pathology
Diagnostic Evaluation
Histopathologically, the RPE adenoma is com-
The clinical features are characteristic. Ultra- posed of proliferating RPE cells. Tumors arising
sonography shows a nodular echodense mass from the anterior portion of the RPE have vacu-
with high internal reflectivity. There is early olated polygonal cells in a glandular or tubular
configuration with a vascularized connective tis- Clinical Features

sue septae (Fig. 5.7). Prominent basement mem-
brane is evident. Tumors demonstrating nuclear Symptoms
atypia and local invasiveness are classified as ade- Patients with adenomas in the macular area may
nocarcinoma. RPE tumors including adenocarci- exhibit visual symptoms including vision loss.
noma are not known to metastasize. Interestingly,
immunohistochemical studies reveal that tumor Signs
cells may co-express melanocytic and epithelial Most RPE adenomas are located in the peripheral
markers [42]. fundus, although rare juxtapapillary tumors have
a b
c d
Fig. 5.7 A 40-year-old woman noted to pigmented fun- cal diagnosis of RPE adenoma was made and patient
dus mass on a routine examination (a). Note dark uniform observed every 3 months. At 6 month visit, the tumor was
color with absence of drusen, orange pigmentation, or noted to have enlarged. Transvitreal FNAB was performed
details of overlying retina. Prominent lipid exudation without significant complications. One-week postopera-
along the base of the tumor was also observed. The retinal tive appearance showing mild retinal hemorrhage at the
vessels seem to lead into the tumor but the vessels were not biopsy site (e). Cytology specimen revealed bland cuboi-
dilated. Fluorescein angiography confirmed that intrinsic dal cells with granules of pigment suggestive of RPE cells
vasculature of the tumor was derived from of retinal vascu- rather than choroidal melanoma (f). Three years after epi-
lature (b). B-scan ultrasonography revealed a dome-shaped scleral brachytherapy (Iodine-125; 85 Gy apical dose), the
lesion that was located anterior to the choroid (c). The tumor regressed with surrounding chorioretinal atrophy
tumor had high internal reflectivity on A-scan (d). A clini- (g). (f: Courtesy of Charles Biscotti, MD)
e f
been reported [14]. In a series of 13 adults an important diagnostic feature, as it is almost

patients with a mean age of 53 years (age range never associated with untreated choroidal
28–79 years), 10 were women and 3 were men; melanoma.
10 were white and 3 were African American [43].
All tumors were solitary and unilateral and Diagnostic Evaluation
ranged from small (2 × 2 × 1 mm) to large in size Fluorescein angiography shows early hypofluo-
(17 × 17 × 17 mm). The tumors are usually soli- rescence and late minimal hyperfluorescence of
tary and unilateral and start as a small, deep reti- the tumor, without visibility of choroidal ves-
nal tumor that is dark brown to black in color sels. Ultrasonography typically demonstrates
(Fig. 5.7). The tumor usually grows very slowly, abrupt elevation of the tumor and medium to
invading the overlying sensory retina, at which high internal reflectivity and acoustic solid-
time it often is associated with a prominent reti- ity. Enhanced depth imaging OCT (EDI-OCT)
nal feeder artery and draining vein that were shows irregular tumor surface with full-thick-
visualized in 8 of the 13 patients, 5 of whom had ness retinal involvement and dense posterior
an exudative retinal detachment. Two patients optical shadowing [45], unlike choroidal mela-
had recurrent vitreous hemorrhage [44]. The noma which is located in the uveal layer [46].
presence of surrounding retinal hard exudates is Nevertheless, the majority of the patients are
Table 5.4 Relative differentiating features of retinal pigment epithelial adenoma and choroidal melanoma
Feature RPE adenoma/adenocarcinoma Choroidal melanoma
Shape Dome Dome or mushroom
Color Black Brown
Margins Sharply demarcated Undemarcated
Retinal feeder vessels Present Absent
Retinal Serous Frequent Frequent
Exudation Lipid Frequent Almost never
Ancillary studies Fluorescein Communication with retinal Intrinsic abnormal choroidal
angiography circulation vasculature
Ultrasonography Medium to high reflectivity Low to medium reflectivity
Behavior Growth Slow Rapid
Metastasis Never Frequent
Histopathology Cells Polygonal cells Spindle or epithelioid cells
Arrangement Glandular arrangement Fascicular or absent
Basement membrane Prominent Absent
Immunohistochemistry Epithelial antigens Melan-A
HMB-45
a b
Fig. 5.8 Longstanding blind eye due to healed toxoplasma retinochoroiditis. Note nodular almost translucent subreti-
nal elevation adjacent to a healed chorioretinal scar (a). Suggestion of osseous metaplasia at the level of the RPE (b)
referred with a suspected diagnosis of choroi- Treatment

dal melanoma. It is not always possible to dif-
ferentiate RPE adenoma and adenocarcinoma A variety of treatment modalities have been used
from choroidal melanoma despite clinical and depending on individual case characteristics,
diagnostic evaluation (Table 5.4). In such cases, including observation, enucleation, local tumor
fine-needle aspiration biopsy that discloses cells resection, irradiation, and laser therapy [43, 49].
of pigment epithelial origin can be diagnostic Observation can be safe in small and asymptom-
(Fig. 5.7). In rare instances, reactive prolifera- atic lesions, whereas in medium/large tumors,
tion of RPE can attain tumorous proportions plaque radiotherapy could be considered. Laser
simulating RPE adenoma and choroidal mela- treatment, thermotherapy, or cryotherapy could
noma (Fig. 5.8) [47, 48]. be good options in the presence of exudation.
Moreover vitrectomy could be added in case of involvement of the optic disc, the papillomacular
vision loss due to vitreoretinal traction. bundle, or the fovea [53]. Secondary causes of
decreased vision include tractional distortion of
the macula and epiretinal membrane formation
Prognosis [53]. Other presenting symptoms include strabis-
mus, floaters, and leukocoria [53].
The visual prognosis is variable. RPE adenoma
may remain stable or enlarge simulating a mela- Signs
noma [44]. They may not respond even to brachy- CHR is usually unilateral and can occur at the
therapy necessitating enucleation [44, 49]. optic disc or elsewhere in the fundus (Fig. 5.9). If
hamartomas are present in both eyes, an underly-
ing systemic syndrome, such as neurofibromato-
ombined Hamartoma of the Retina
C sis type 2, has to be suspected [54]. The tumor is
and RPE gray-black in color, and the lesion typically has
an epiretinal membrane that may cause retinal
Introduction traction, and there may be associated tortuous or
straightened retinal blood vessels, probably due
Combined hamartoma of the retina and retinal to secondary excessive glial tissue on the surface
pigment epithelium (CHR), a term first coined by of the lesion [55]. The traction may be progres-
Gass, is a rare developmental disorder involving sive, leading to a decline in vision.
the retina and the retinal pigment epithelium [50]. Hamartomas are generally stable, but exces-
sive glial proliferation can lead to retinal traction
and visual loss [55]. CHRs do not undergo malig-
Etiology and Pathogenesis nant transformation. Uncommon secondary
effects include choroidal neovascularization, vit-
Hamartomas are benign proliferation of tissues that reous hemorrhage, retinoschisis, and formation
are normally present in the affected area. Although of a macular hole [56].
there is an association between CHR and NF2 [51],
the mechanistic relationship remains to be eluci- Association
dated. Diagnosis of CHR in infants supports the Although most cases of CHR are isolated, there
congenital nature of the lesions, but there have also have been reports of associated systemic disor-
been reports of acquired cases of CHR; Ticho et al. ders. In his original report, Gass noted that one of
reported the development of CHR in a 3-year-old his patients had multiple café-au-lait spots [50],
patient following parainfectious meningoencepha- and there is another reported occurrence of CHR
litis with optic neuritis [52]. in NF1 [57]. However, the most frequent associa-
tion of CHR is with NF2 [51, 58]. Sporadic
observations of CHR in several syndromes such
Pathology as branchio-oculo-facial syndrome [59], Gorlin
syndrome [60], and ipsilateral Poland anomaly
CHR is usually composed of varying amounts of have also been reported [61].
vascular, glial, and pigment epithelial components.
Clinical Features
CHR can be mistaken for malignancies such as
Symptoms retinoblastoma or choroidal melanoma, and there
The most common presenting symptom of CHR have been patients who were enucleated because
is painless decrease in vision usually due to direct of the suspicion of a malignant lesion. CHR can
a b
c d
Fig. 5.9 Combined hamartoma of the retina and RPE nent epiretinal membrane (c). Fluorescein angiography
usually appears as a unilateral gray-black-colored lesion demonstrated leakage within fine retinal vessels and
(a). Temporal dragging the vessels is evident on the exam- hypofluorescence corresponding to the pigment prolifera-
ination of the posterior pole (b). OCT showing normal tion at the margin (d)
RPE layer, disorganization of retinal layers, and promi-
often be reliably diagnosed on indirect ophthal- architecture which is useful in differentiating

moscopy. Ancillary studies such as fluorescein from a minimally elevated choroidal melanoma,
angiography and OCT are helpful in establishing which shows normal retinal architecture [62].
the diagnosis. Angiographically, the lesion shows Although often isolated, patients diagnosed with
blockage of the choroidal fluorescence due to CHR should undergo evaluation to exclude sys-
increased pigmentation of the retina pigment epi- temic association, especially NF2.
thelium. Vascular tortuosity is prominent in the
arterial phase and progressive hyperfluorescence
is evident in the late phase due to leakage from Treatment
the abnormal vessels [53]. Optical coherence
tomography of CHR demonstrates full-thickness Most CHR cause decreased vision because they
irregular highly reflective lesion of the inner ret- involve the macula and peripapillary region and
ina with obscuring of the underlying retinal lead to retinal traction and distortion. CNV can
be treated with laser or submacular surgery. 7. Buettner H. Congenital hypertrophy of the retinal
pigment epithelium. Am J Ophthalmol. 1975;79(2):
Peeling of the epiretinal membrane may not pos- 177–89.
sible in cases where the membrane is tightly 8. Cleary PE, Gregor Z, Bird AC. Retinal vascular changes
adherent or even part and parcel of the retina, and in congenital hypertrophy of the retinal pigment epi-
the role of vitrectomy and membrane peel thelium. Br J Ophthalmol. 1976;60(7):499–503.
9. Santos A, Morales L, Hernandez-Quintela E, et al.
remains controversial in management of vision Congenital hypertrophy of the retinal pigment epithe-
loss in CHR. However, vitrectomy and mem- lium associated with familial adenomatous polyposis.
brane peeling have been used in selected cases Retina. 1994;14(1):6–9.
with modest visual improvement, especially in 10. Shields CL, Mashayekhi A, Ho T, et al. Solitary con-
genital hypertrophy of the retinal pigment epithelium:
those in which the hamartoma has not involved clinical features and frequency of enlargement in 330
the full thickness of the retina in patients with vit- patients. Ophthalmology. 2003;110(10):1968–76.
reous hemorrhage and preretinal gliosis [63]. 11. Shields JA, Eagle RC Jr, Shields CL, et al. Malignant
Hence OCT can be very useful in determining the transformation of congenital hypertrophy of
the retinal pigment epithelium. Ophthalmology.
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Tumors of the Ciliary Epithelium
6
Javier Elizalde, María de la Paz, Rafael I. Barraquer,
and Arun D. Singh
Introduction inner layer, adjacent to the vitreous cavity, is the

nonpigmented epithelium, which is cuboidal or low
Tumors arising from the ciliary epithelium are columnar and which lines the surface of the ciliary
rare. The extremely low prevalence of these crests, extending posteriorly to be continuous with
tumors often causes them to be mistaken for the sensory retina. The nonpigmented epithelium
other more common iridociliary tumors such as produces aqueous humor and possibly the hyal-
melanoma or uveal metastases. The location of uronic acid found within the vitreous gel.
these rare lesions growing behind the iris, the
complexity in differentiating between benign
and malignant tumors, their remarkable cellu- Classification
lar polymorphism, and the possibility of deal-
ing with either a congenital or acquired tumor Based on Zimmerman’s histological classifica-
make their diagnosis difficult [1–3]. tion, ciliary epithelial tumors may be grouped as
congenital and acquired (Table 6.1) [1].
Anatomy
Congenital Tumors of Ciliary
The epithelium of the pars plana and the pars plicata Epithelium
has two layers. The outer layer is the pigmented
epithelium, which is continuous anteriorly with the The congenital tumors of the ciliary epithelium
sphincter and dilator muscles of the iris and pos- arise from the primitive medullary epithelium,
teriorly with the retinal pigment epithelium. The before its differentiation into its various adult
derivatives. Thus, they tend to become clinically
apparent in young children and to have an embry-
onic appearance histologically.
J. Elizalde (*) · M. de la Paz · R. I. Barraquer

Glioneuroma
Centro de Oftalmología Barraquer, Barcelona, Spain
A. D. Singh
Glioneuroma is perhaps the rarest tumor in the
Cole Eye Institute, Cleveland Clinic, group, with only a few cases reported in the lit-
Cleveland, OH, USA erature [4–7]. It is considered to be a choristoma

72 J. Elizalde et al.
Table 6.1 Histological classification of ciliary epithelium tumors

Congenital Glioneuroma
Medulloepithelioma Teratoid Benign
Malignant
Nonteratoid Benign
Malignant
Acquired Pseudoadenomatous hyperplasia Reactive
Age-related (Fuchs’ or coronal adenoma)
Adenoma
Adenocarcinoma
arising from the anterior margin of the primitive [8], this tumor came to be known as medullo-
optic cup, without any neoplastic potential. epithelioma, as proposed by Grinker in 1931
[9]. Intraocular medulloepithelioma is a non-
Clinical Features hereditary, embryonal neoplasm that usually
Glioneuroma appears as a slowly enlarging white occurs in the ciliary body. Accordingly, it con-
or fleshy unilateral mass in the inferior angle of tains pure neuroepithelial structures (nontera-
the anterior chamber, often with involvement of toid medulloepithelioma or diktioma) or, more
the corneoscleral limbus. The tumor can be adher- commonly, derivatives of the medullary epi-
ent to the corneal endothelium and can displace thelium, particularly cartilage, skeletal muscle,
the pupil and the lens or induce a cataract [4, and brain tissue [2, 10].
6, 7]. An associated ciliary body colobomatous
defect may be present. The intraocular pressure Clinical Features
may be elevated [4, 7]. Glioneuroma is usually Medulloepithelioma is typically a disease of
recognized at birth or shortly after, although it childhood that is usually diagnosed during the
has been diagnosed in a 21-year-old woman [4]. first decade of life, although some cases are
asymptomatic until adulthood [11–13]. The most
Pathology relevant clinical signs and symptoms of medullo-
Glioneuroma infiltrates the stroma of the iris epithelioma are poor vision, pain, leukocoria, and
and ciliary body and may invade the choroid, the the presence of an intraocular mass appearing
peripheral retina, and also extrasclerally [4, 6, 7]. behind the pupil (Box 6.1). The tumor is an irreg-
Light microscopy reveals a well-differentiated ular, variable-sized, white or gray, translucent
neural tissue similar to the brain, with eosino- mass arising from the ciliary region in contact
philic fibrillary material, axonal processes, and with the iris (Fig. 6.1). It is frequently vascular-
glial cells within the tumor matrix [6]. ized and rarely pigmented. One well-known clin-
ical feature of medulloepithelioma is the presence
Management of cysts within the tumor [2, 10, 14]. Large cysts
Because intraocular glioneuroma is rare, there is no may break off from the tumor and float freely in
clearly established treatment. Most recorded cases the anterior chamber or into the vitreous cavity
have been managed by enucleation of the involved (Fig. 6.2). Iris neovascularization is a common
eye. Glioneuroma has been removed by iridocy- and early finding in eyes with medulloepitheli-
clectomy [4]. Safety and efficacy of diagnostic oma [10]. Children with neovascularization of
biopsy in such cases has not been established. iris of unknown cause should be evaluated to
exclude underlying medulloepithelioma [15].
The presence of a sectorial or total cataract,
Medulloepithelioma with or without subluxation, is common. One of
the earliest clinical manifestations may be a
First described by Verhoeff as a teratoneu- peculiar notch in the lens, producing a “lens colo-
roma [8] and later by Fuchs as a diktyoma boma” in the quadrant of the tumor [2, 10, 11,
6 Tumors of the Ciliary Epithelium 73
a b
Fig. 6.1 Medulloepithelioma of the ciliary body. Translucent mass behind the iris and invading the anterior chamber
through the iris root. Note a dense anterior polar cataract (a, arrow). Same eye with the dilated pupil (b)
14–16]. Other findings include a cyclitic neoplas- Pathology

tic membrane, uveitis, hyphema, retinal detach- According to Zimmerman’s classification,
ment, vitreous hemorrhage, optic nerve invasion, medulloepithelioma may be divided into non-
and extraocular extension of the tumor (Fig. 6.3) teratoid and teratoid types, and either type can
[10]. In adults, medulloepithelioma can resemble have benign or malignant cytologic features
a uveal melanoma [12]. [1, 2, 19]. The nonteratoid medulloepithelioma
Local invasion and extraocular extension occur contains multilayered sheets of cords of poorly
frequently, but metastasis is uncommon and does differentiated neuroepithelial cells that are
not occur in absence of extraocular extension [2, histologically similar to the embryonic retina
17, 18]. and ciliary epithelium. In contrast to the non-
teratoid medulloepithelioma, the teratoid type
demonstrates variable degrees of heteroplasia
Box 6.1 Diagnostic Features (hyaline cartilage, rhabdomyoblasts, undiffer-
of Medulloepithelioma entiated mesenchymal cells resembling embry-
onal sarcoma, neuroglial tissue resembling the
brain, and ependymal structures) [2, 10, 11,
• Manifests during the first decade of life 14, 20]. The rhabdomyoblastic component may
• Should be considered in the differential completely replace the neuroepithelium, to the
diagnosis of leukocoria extent of resembling primary intraocular rhab-
• White or gray translucent mass arising domyosarcoma [18].
from the ciliary body It can be difficult to classify medulloepithe-
• Presence of cysts within the tumor, ante- lioma as benign or malignant. The histopatho-
rior chamber, or vitreous cavity logic criteria of malignancy as defined by
• Iris neovascularization, lens coloboma, Broughton and Zimmerman are areas com-
sectoral or total cataract posed of poorly differentiated neuroblastic
• Other findings include a cyclitic neo- cells; greater pleomorphic or mitotic activity;
plastic membrane, uveitis, hyphema, sarcomatous areas resembling a chondrosar-
retinal detachment, and vitreous coma, rhabdomyosarcoma, or embryonal sar-
hemorrhage coma; and invasion of the uvea, cornea, or
sclera, with or without extraocular invasion
a b
Fig. 6.2 Anterior chamber cysts secondary to medullo- layer of the iris, another one behind the iris, and some
epithelioma of the ciliary body (a). Multiple cysts within cysts near the ciliary body (c, hematoxylin-eosin ×75).
the anterior chamber and emerging through the pupil (b, Photomicrograph showing an irregular cyst on posterior
gonioscopic photographs). Histopathologic composite surface of the corneal endothelium (d, hematoxylin-
photograph showing a cyst adherent to the anterior border eosin ×35)
[2]. More recently, Verdijk has proposed grad-

ing medulloepithelioma as grade 1 (benign), Management
grade II (tumor progression as evidenced with In most cases, the diagnosis is suspected clinically
pleomorphism, increased mitotic activity, and and confirmed by enucleation [17]. Rare cases in
local invasion), and grade III (tumors with adults may be diagnosed with fine needle aspira-
metastatic potential – presence of extrascleral tion biopsy [22]. Because most of these tumors are
extension or metastasis) [21]. cytologically malignant, infiltrating the adjacent
[26–28]. Additional features of the familial syn-

drome include lung cysts, neuroblastoma, cystic
nephroma, Wilms tumor, and rhabdomyosarcoma
[28]. Somatic mutations of DICER1 and KMT2D
are frequent in intraocular medulloepithelioma
[29]. The presence of medulloepithelioma should
be considered in a child with a history of PPB and
vice versa [26, 30].
Acquired Tumors of the Ciliary

Epithelium
In contrast to the congenital tumors that arise from

undifferentiated medullary epithelium, acquired
Fig. 6.3 A 38-month-old girl presented with leukocoria
tumors arise from fully differentiated ciliary epi-
of 2-month duration. On examination, lens coloboma and
a vascularized retrolental sheet (cyclitic membrane) were thelium and usually occur in older patients. These
noted. A pigmented mass was seen in the ciliary body tumors can take the form of reactive proliferations
region from 6 to 8 o’clock position. Tumor recurred after (pseudoadenomatous hyperplasia) or neoplastic
excision necessitating enucleation. Histopathologically,
proliferations (adenoma or adenocarcinoma).
the lesion was confirmed to be malignant teratoid
medulloepithelioma. (Reprinted from Singh et al. [15].
With permission from Slack Incorporated)
Pseudoadenomatous Hyperplasia
(Reactive Proliferation)
vitreous, and proliferating in delicate sheets, which
may not be evident intraoperatively, enucleation of ge-Related Hyperplasia (Fuchs’ or
A
the affected eye is usually advisable [17]. In care- Coronal Adenoma)
fully selected small tumors (<3 clock hours), local Fuchs’ adenoma represents an acquired lesion
removal by iridocyclectomy may be considered as that seems to be age-related, with increasing
an initial management option, although local recur- frequency in older patients [31]. It is com-
rence is usual [17]. Brachytherapy might be a good monly observed as an opaque white mass usu-
option in circumscribed tumors, with the stipulation ally confined to a ciliary process and tends
of a possible retreatment in case of tumor recur- to be noted incidentally, in eyes removed
rence [23–25]. Distant metastasis does not respond surgically, or postmortem (Fig. 6.4) [32].
to radiation therapy or chemotherapy [3]. Histologically, it is composed of irregular
cords of cells of the nonpigmented ciliary epi-
Pleuropulmonary Blastoma thelium with abundant acellular eosinophilic
An association with pleuropulmonary blas- basement membrane (Fig. 6.5) [33]. In rare
toma (PPB) has been recently reported by instances, the tumor can erode into the ante-
the International Pleuropulmonary Blastoma rior chamber, simulating an iridociliary tumor
Registry [26]. PPB is a rare embryonic tumor such as melanoma [31, 33, 34].
(analog of retinoblastoma, neuroblastoma,
Wilms tumor) arising from primitive pleuro- Reactive Hyperplasia
pulmonary tissue and presenting as a lung and The nonpigmented ciliary epithelium contrib-
pleural tumor in early childhood [27]. PPB may utes to the development of a cyclitic membrane,
be part of a familial cancer syndrome caused composed of a proliferation of benign cells from
by DICER 1 mutation on chromosome 14q31 the nonpigmented ciliary epithelium, connective
a b
c d
Fig. 6.4 Fuchs’ adenoma (clinical). Slit lamp colored tudinal scan at 3 o’clock, 40 MegaHertz) showing ciliary
picture with pigmented tumor present at ∼3:30 eroding body tumor with scale from 0 to 5 mm (c). Appearance of
through the iris root (a). Gonioscopy demonstrating two the eye 2 years postoperatively (d). (Reprinted from
foci of pigmented tumor extending through ciliary body Nagarkatti-Gude et al. [33]. With permission from
band and iris root (b). Ultrasound biomicroscopy (longi- Elsevier)
tissue, and blood vessels. Clinically it is charac- Adenoma and Adenocarcinoma

terized by a dense retrolental fibrovascular tissue of the Ciliary Epithelium
that usually extends from the pars plicata on one
side to the pars plicata on the other side. It usu- True acquired neoplasms of the pigment or non-
ally does not take the form of a distinct tumor but pigmented ciliary epithelium are rare. They may
rather occurs as a thickened sheet or membrane be benign (adenoma) or malignant (adenocarci-
[35]. Reactive hyperplasia of the ciliary epithe- noma), and the clinical differentiation between
lium is usually seen in histopathologic specimens the two may be impossible. Similar tumors arise
of traumatized or disorganized eyes and may from the pigment epithelium in the iris [37] and
adopt a pseudotumor appearance [35, 36]. the retinal pigment epithelium [38].
mented ciliary epithelium are gray-white (i.e.,

a
amelanotic) (Fig. 6.7) [39, 43]. These tumors
can be asymptomatic or can cause painless
visual loss. Adenoma and adenocarcinoma of
the ciliary body have an irregular and some-
times multilobulated surface [39–41, 43]. Uveal
melanoma tends to present with a mushroom-
like growth pattern. Some tumors may present
with cells in the anterior chamber and with sen-
tinel vessel in the overlying episclera – though
this finding is more characteristic of uveal mela-
noma. Pigment dispersion over the iris surface
and into the vitreous is also seen more often
with adenoma of the ciliary pigment epithelium
than with melanoma [42, 44]. Adenoma of the
b
nonpigmented ciliary epithelium may be asso-
ciated with iris or disc neovascularization due
to excessive production of vascular endothelial
factor [45]. It is not uncommon to observe dys-
coria and secondary cataract formation induced
by tumor compression, which can also cause
lens subluxation. Although there are no large
series on record, most acquired tumors arising
from the ciliary epithelium appear to have a
relatively benign course. The tumors may grow
slowly and destroy the ocular structures, but
they almost never metastasize or cause death
unless there has been extraocular extension [36].
Examination of phthisical eyes can unexpect-
Fig. 6.5 Fuchs’ adenoma (histopathology). A 60-year-
edly reveal adenocarcinoma of the pigmented
old man who underwent subtotal orbital exenteration for
intraorbital spread of basal cell carcinoma. An incidental [46] or nonpigmented ciliary epithelium [36, 47,
adenomatous proliferation can be seen on the nonpig- 48]. However, the causal relationship between
mented ciliary epithelium with hematoxylin and eosin presence of the tumor and phthisis is not well
staining (a, arrow). The lesion consists of amorphous
understood. It is possible that factors that lead
eosinophilic material and mucopolysaccharides (b).
(Reprinted from: Surapaneni et al. [32]. With permission to phthisis such as chronic inflammation induce
Elsevier) tumor formation rather than presence of tumor
leading to phthisis [46]. All phthisical eyes that
undergo evisceration or enucleation should
Clinical Features be subjected to histopathologic examination
Both adenoma and adenocarcinoma appear as a [47]. Features differentiating adenoma from
solid ciliary body mass, associated with second- melanoma of the ciliary body are summarized
ary cysts [39] that present with variable char- (Table 6.2).
acteristics and simulate ciliary body melanoma.
Tumors arising from the pigment ciliary epithe- Pathology
lium are usually deeply pigmented (Fig. 6.6) These tumors are composed of pigmented
[40–42], and tumors arising from the nonpig- or nonpigmented cuboidal or columnar cells
a b
Fig. 6.6 Adenoma of the pigmented ciliary epithelium. circumscribed mass (b). (Reprinted from Chang et al.
Clinical features. Slit lamp photograph (a). Clinical [42]. With permission from John Wiley & Sons)
images. Ultrasonographic biomicroscopy showing a solid
a b
Fig. 6.7 Adenoma of the nonpigmented ciliary epithe- chromatic nuclei. The tumor cells are arranged in tubular,
lium. Slit lamp photograph demonstrating an anterior dis- papillary, and solid pattern. (d, hematoxylin-eosin × 75).
placement of the iris (a). A predominantly amelanotic The tumor cells, which are arranged in a tubular or glan-
nodular mass is located behind the iris (b). Histopathologic dular pattern, are surrounded by thick basement mem-
macroscopic photograph discloses a tumor of the nonpig- brane material (e, stain, periodic acid-Schiff;
mented epithelium extending from the anterior aspect of magnification, × 300). The neoplastic cells show positive
the ciliary processes and to the posterior surface of the iris reactivity to CAM 5.2. Immunoperoxidase staining (f,
and also a tumor located in the ciliary body and the root of stain, avidin-biotin complex technique; magnification,
the iris (c, hematoxylin-eosin × 35). Microscopic struc- × 300). (e, f: Reprinted from: Laver et al. [36]. With per-
ture of the tumor composed of cuboidal and columnar mission from Elsevier)
cells with abundant eosinophilic cytoplasm and hyper-
c d
e f
Table 6.2 Relative differentiating features of adenoma (adenocarcinoma) and melanoma of the ciliary body
Feature Adenoma Melanoma
Clinical Shape Irregular, multilobulated Smooth dome, mushroom
Color Melanotic or amelanotic Melanotic or amelanotic
Sentinel vessels Frequent Infrequent
Anterior chamber inflammation Frequent Infrequent
Pigment dispersion in vitreous Frequent Infrequent
Cyst/cavities Frequent Infrequent
Growth Slow Rapid
Histopathological Origin Epithelial Stromal
Composition Cuboidal or columnar cells Spindle or epithelioid cells
Pattern Arranged in cords or tubules No specific pattern
Vimentin Positive Negative
HMB 45 Negative Positive
Behavior Neoplasia Usually benign, may be malignant Always malignant
Metastasis Never Frequent
usually arranged in cords or tubules with a cysts, iris neovascularization, lens coloboma, or
thick basement membrane [36, 42, 46, 49]. cataract. The presence of medulloepithelioma
Adenocarcinomas exhibit more malignant fea- should be considered in a child with a history
tures, such as cellular proliferations and loss of of PPB and vice versa. Acquired neoplasms of
alveolar characteristics [50–52]. In addition, the pigmented or nonpigmented ciliary epithe-
evidence of choroidal invasion and extraocu- lium may be benign (adenoma) or malignant
lar extension suggest adenocarcinoma rather (adenocarcinoma), and the clinical differentia-
than adenoma [46]. Positivity of the tumor tion between the two may often be impossible.
cells to vimentin confirms the nonpigmented Both adenoma and adenocarcinoma appear as a
ciliary epithelial origin [36, 53]. In some cases, solid ciliary body mass simulating a ciliary body
immunopositivity with antibodies targeted to melanoma. These tumors may grow slowly and
different cytokeratins may be also observed, destroy the ocular structures, but they almost
although this pattern tends to be highly vari- never metastasize. If clinically suspected, these
able. Immunoreactivity to HMB-45, which is tumors are often managed by local resection
typical of melanoma, proves negative in these (iridocyclectomy), episcleral brachytherapy, or
cases [36, 48, 49, 53]. enucleation.
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Primary Central Nervous System
and Retinal Lymphoma
7
Mary E. Aronow, Manmeet S. Ahluwalia,
David M. Peereboom, and Arun D. Singh
Introduction forms of ocular lymphoma that affect the

adnexal structures and/or uveal tract is impor-
Primary central nervous system lymphoma tant, as the latter are most commonly indolent,
(PCNSL) is an aggressive, extra-nodal non- B-cell lymphomas that behave similarly to their
Hodgkin’s lymphoma (NHL). This predomi- systemic counterparts [2].
nantly B-cell malignancy is associated with
a median survival ranging from 1 to 8 years
depending on factors such as age and Karnofsky Pathogenesis
performance status [1]. PCNSL originates in
the brain parenchyma, spinal cord, leptomen- PCNSL is believed to originate from late germi-
inges, and eyes. Formerly used descriptors nal center or post-germinal center lymphoid
such as “reticulum cell sarcoma” and “micro- cells; however, the neurotropic mechanism by
gliomatosis” are no longer used as both mis- which these cells localize to the central nervous
leadingly imply that the malignancy arises system (CNS) remains uncertain. As the CNS
from transformed reticulum or microglial cells. and eyes lack lymphatic networks, it has been
Vitreoretinal lymphoma (VRL) is a variant of hypothesized that the trafficking of lymphoma
PCNSL characterized by ophthalmic involve- cells from the brain to the eye and vice versa
ment. The distinction between VRL and other involves either invasion of the optic nerve or
seeding through a shared vascular supply [3].
Animal models have the potential to improve
our current understanding of lymphoma patho-
M. E. Aronow (*) genesis in humans. Early work in this area
Massachusetts Eye and Ear, Ocular Melanoma Center focused on murine models created by intraperito-
and Retina Service, Harvard Medical School, Boston, neal or intravitreal injection of T-cell lymphoma,
MA, USA
e-mail: [email protected] while more recent murine models have used
human B-cell lymphoma cell lines in order to
M. S. Ahluwalia · D. M. Peereboom
The Rose Ella Burkhardt Brain Tumor & more closely mimic the human disease state [4].
Neuro-Oncology Center, Cleveland Clinic, Cleveland, Intravitreal injection of human B-cell lymphoma
OH, USA (cell line CA46) into severe combined immuno-
A. D. Singh deficient (SCID) mice sacrificed at sequential
Department of Ophthalmic Oncology, time points revealed tumor infiltration first at the
Cole Eye Institute, Cleveland Clinic,
retinal surface, followed by migration through
Cleveland, OH, USA

84 M. E. Aronow et al.
the retina and progression through the subretinal younger individuals. Intraocular involvement
space, and eventually spread to the choroid and may precede, occur simultaneously, or follow the
the CNS [5]. While choroidal involvement is seen CNS disease. Intraocular involvement is the pre-
in animals, lymphoma cells typically do not cross senting feature in VRL, and subsequent CNS
Bruch’s membrane in humans. involvement develops in 56–85% of patients over
There are no known risk factors in immuno- a period of 8–29 months [12]. Conversely, nearly
competent individuals; however, congenital 25% of patients with PCNSL will have concomi-
immunodeficiency and iatrogenic or acquired tant vitreoretinal lymphoma at the time of CNS
immunosuppression such as human immunodefi- diagnosis [13].
ciency virus (HIV) and acquired immune defi-
ciency syndrome (AIDS) are risk factors. PCNSL
develops in as many as 6% of patients with AIDS Symptoms
[6]. Epstein-Barr virus infection of B lympho-
cytes in the absence of T-cell suppressor function Ophthalmic
(due to immunosuppression) leads to an uncon- Patients may be asymptomatic, but up to 50%
trolled lymphocytic proliferation [7]. While the present with painless blurred vision, floaters,
vast majority of PCNSL are of the diffuse large or both. Bilateral involvement occurs in up to
B-cell lymphoma subtype, rare cases can be sec- 80% of cases and is typically asymmetric [12].
ondary to human T-cell lymphotropic virus type Asymptomatic individuals may be diagnosed
1 (HTLV-1) infection [8]. at the time of ophthalmic screening in the set-
ting of known PCNSL. Owing to the nonspe-
cific nature of the ophthalmic manifestations, a
Clinical Features diagnosis of VRL is difficult to make on clini-
cal grounds alone, and delay in diagnosis is
Epidemiology common. An average time of 2 years from
onset of symptoms to histopathologic confir-
PCNSL represents about 1–2% of extra-nodal mation of diagnosis of 2 years has been
lymphomas and 4–6% of primary brain tumors. reported [14].
The age-adjusted annual incidence of PCNSL is
approximately 4.8 per million population in the entral Nervous System
C
United States. Until a few decades ago, this The brain, spinal cord, and leptomeninges either
tumor was best known among patients with separately or in various combinations can be
AIDS as a manifestation of late-stage disease. involved. Solitary involvement of the spinal cord
With the advent of highly active antiretroviral is rare. Personality changes are a common pre-
therapy (HAART), the incidence has decreased senting feature because the frontal lobe is the
significantly in this population. However, the most frequently involved region of the brain.
incidence among immunocompetent patients Seizures are an uncommon feature.
has been rising, for unclear reasons [9]. While
VRL is frequently seen in the setting of PCNSL,
the incidence is unknown due to the paucity of Clinical Features
cases. Between 1999 and 2002, approximately
100 new cases of VRL were reported in the Ophthalmic
United States [10]. Anterior segment findings in VRL are rare and
Among immunocompetent individuals, the are also nonspecific but include keratic precipi-
peak incidence of PCNSL occurs between the tates, aqueous cells, and aqueous flare. The hall-
fifth and seventh decades, with a mean age of mark feature is vitreous cells (present in up to
60 years at diagnosis [11]. In the immunocom- 50% of cases), combined anterior and vitreous
promised population, the disease occurs in cells (22% of cases), and subretinal pigment epi-
7 Primary Central Nervous System and Retinal Lymphoma 85
thelial (RPE) infiltrates (18% of cases) [15]. meninges. Leptomeningeal disease is present in
Clumps of cells in the vitreous with an “aurora up to 40% of cases [16]. Brain lesions can be
borealis” appearance are a common finding. multifocal, particularly in immunosuppressed
Multifocal subretinal pigment epithelial infil- individuals.
trates are considered to be pathognomonic
(Fig. 7.1). Rarer findings include perivasculitis,
retinal artery occlusion, optic atrophy, and exuda- Diagnostic Evaluation
tive retinal detachment (Table 7.1).
Diagnostic evaluation should begin with a thor-
entral Nervous System
C ough history, focused on ocular symptoms,
PCNSL is a rapidly growing tumor, and diagno- changes in cognitive functioning, neurological
sis is often established within a few months of the deficits, and risk factors for immunosuppression.
onset of symptoms. The lesions in the CNS tend A complete ophthalmic examination of both the
to be periventricular in location, thus allowing anterior and posterior segments is required to
access to cerebrospinal fluid (CSF) and lepto- assess disease extent and laterality. Fundus auto-
a b
c d
Fig. 7.1 Slit-lamp photograph showing keratic precipi- ophthalmoscopy (d), and subretinal pigment epithelium
tates (a), vitreous cells on transillumination (b), large infiltration by optical coherence tomography (e).
clumped vitreous cells on optical coherence tomography Fluorescein angiography reveals multiple hyperfluores-
(c), creamy subretinal pigment epithelium infiltrates on cent pinpoint foci scattered throughout the fundus (f)
Table 7.1 Chemotherapy for treatment of primary vitreoretinal lymphoma (VRL)a

Cases/ Treatment method Response
Author Year eyes Indication Route Agent (%) Side effects (%)
Fishburne 1997 47 eyes Recurrent Intravitreal with BBB MTX 100 Visual loss (15)
400 μg
Sandor 1998 14 Intravenous + intrathecal MTX, thiotepa, 79 Recurrence (71)
vincristine, Neurotoxicity (14)
cytarabine
Soussain 2001 22 Refractory/ Intravenous Multiagent 75 Recurrence (10)
recurrent chemotherapy Neurotoxicity (35)
with stem-cell
rescue
Smith 2002 16/26 Initial Intravitreal MTX 400 μg 100 Recurrence (12)
eyes Cataract (73)
Epitheliopathy (58)
Maculopathy (42)
Vitreous hem (8)
Optic atrophy (4)
Endophthalmitis (4)
Batchelor 2003 9 Initial Intravenous MTX 78 Recurrence (40)
High dose
Kitzmann 2007 5 Initial Intravitreal + intravenous Rituximab + MTX 100 None
Frenkel 2008 26/44 Initial/ Intravitreal MTX 400 μg 91 Conjunctival
eyes recurrent hyperemia and
some form of
keratopathy (100)
Soussain 2008 43 Refractory/ Intravenous Multiagent 61 Treatment-related
recurrent chemotherapy mortality (~10)
with stem-cell
rescue
Jahnke 2009 10 Initial/ Intravenous/oral Ifosfamide or 90 Thrombocytopenia or
recurrent trofosfamide leukopenia (40)
Hashida 2012 20 eyes MTX Intravitreal Rituximab 100 IOP increase (60)
intolerance Iridocyclitis (35)
Larkin 2014 48 eyes Initial/ Intravitreal Rituximab and/or 65 Recurrence (23)
refractory MTX
Riemens 2015 21 Initial Intravitreal + intravenous Multiagent ––– Recurrence (36)
chemotherapy Renal failure (10)
Akiyama 2016 10 Initial Intravitreal + intravenous MTX 100 Recurrence (40)
Shields 2017 3 eyes Initial Intravitreal Melphalan 100 None
Abu 2018 51 eyes Initial Intravitreal + intravenous MTX and/or 100 –––
Samra rituximab
Abbreviations: BBB blood-brain barrier disruption with mannitol, MTX methotrexate
Excludes single-case reports
a
fluorescence (AF) is helpful in diagnosis and in which can be appreciated on optical coherence
monitoring progression of vitreoretinal lymphoma tomography (OCT) [19]. After treatment, as active
[17]. Active lesions appear as hyper-AF lesions as lesions become inactive (atrophic), the AF pattern
compared with inactive (atrophic) lesions that correspondingly changes from that of hyper-AF to
appear as hypo-AF. In general, hyper-AF lesions hypo-AF (Fig. 7.2) [20].
correspond with hypofluorescent appearance on The relationship between VRL and PCNSL is
the fluorescein angiography [18]. The hyper-AF is variable with intraocular involvement preceding,
explained on the basis of RPE and photoreceptor occurring simultaneously, or following CNS
disruption by the sub-RPE lymphoma infiltrates, manifestations. It is therefore recommended that
a b
Fig. 7.2 Fundus photograph of vitreoretinal lymphoma F (large arrow) as compared with inactive (atrophic)
A
(a). Note active lesion (large arrow) and inactive atrophic lesions that appear hypo-AF (b, small arrow). The hyper-
lesions (small arrow). With AF using green laser source AF is explained on the basis of RPE and photoreceptor
(532 nm, Optos system), the active lesion appears hyper- disruption by the sub-RPE lymphoma infiltrates (c)
individuals with VRL undergo a thorough evalu- diagnostic techniques exist, including vitreous,
ation by a medical oncologist to exclude CNS retinal, and subretinal biopsy. Neoplastic cells
involvement at the time of initial diagnosis and can be identified by an experienced cytologist,
periodically thereafter (Fig. 7.3). Similarly, peri- using an array of techniques such as liquid-based
odic ophthalmic examinations should be part of cytology, cytospin, and cell block preparations
the diagnostic evaluation and subsequent man- stained with modified Papanicolaou, Giemsa, or
agement of individuals diagnosed with PCNSL. standard hematoxylin and eosin stains (Fig. 7.4).
When analyzing fresh samples, proper and rapid
handling of vitreous samples is critical, as aspi-
Ophthalmic rates are generally of low cellularity and neoplas-
tic cells undergo rapid lysis. The laboratory
In the absence of known PCNSL, the diagnosis of should therefore be informed of the impending
VRL may be suspected based upon clinical fea- arrival of the specimen even before the biopsy is
tures, but diagnosis relies on confirmatory histo- performed. If a delay of more than 1 h is antici-
pathology. Biopsy should be considered in pated, then a mild fixative, such as CytoLyt,
middle-aged or elderly patients with “idiopathic” should be used.
uveitis, particularly in cases that are initially Diagnostic pars plana vitrectomy is frequently
responsive to steroids but are recurrent. Several performed for diagnostic confirmation. A com-
Vitrectomy
Undiluted
Diluted
1 ml
Thin Prep
Flow PCR: Gene

Cytospin Cell Block
Cytometry Rearrangement
Limited Lymphoma
Immunohistochemistry Immunohistochemistry
Panel: CD 19, 20, 22
Conclusive Equivocal
Fig. 7.3 Schema for analysis of vitreous samples for sus- diluted vitreous sample is divided into four portions for
pected lymphoma. Initial undiluted vitreous specimen cytospin, cellblock, and flow cytometry. Gene rearrange-
(about 1 ml) is processed by ThinPrep for liquid-based ment studies are performed if the flow cytometry results
cytology because it preserves the cellular details. The are equivocal. (Based on data from Rishi et al. [21])
mon technique is to obtain an undiluted vitreous

sample of about 1–2 ml prior to the start of the
infusion during vitrectomy. Some surgeons
indent the globe to do this and others inject air.
Following collection of the first sample, the infu-
sion fluid is started, and a second diluted speci-
men is obtained using gentle vitreous cutting.
Some centers submit the vitreous cassette as a
third sample. If being processed fresh, specimens
should be delivered to the laboratory within 1 h
of surgery. Failure is not uncommon. Multiple
vitreous biopsies may need to be performed
before a definitive diagnosis is established. There
is recent interest in using 25-gauge sutureless vit-
rectomy for diagnostic purposes, and these tech-
Fig. 7.4 Vitrectomy sample containing large atypical niques may improve patient comfort and decrease
lymphocytes, necrotic lymphoid cells, and nuclear debris. operative times. This technique has been used
Inset shows characteristic nuclear membrane protrusions
and a prominent nucleolus (main figure, Millipore filter, with success in some centers [22].
hematoxylin, and eosin; original magnification Å ~ 250). When vitreous cells are minimal or absent and
(Courtesy of Ralph C. Eagle Jr., MD) subretinal pigment epithelial infiltrates are the pre-
dominant feature, a chorioretinal biopsy may be these markers. An elevated ratio of interleukin-10
preferable. A technique has been described, where (IL-10) to interleukin-6 (IL-6) has been shown to
an initial core vitrectomy is performed allowing be suggestive of VRL [29]. While helpful as sup-
access to the subretinal infiltrate. Vitreous separa- portive evidence for diagnosis, the interleukin
tion is induced, and thorough vitrectomy is per- ratio alone as a diagnostic tool is not clearly estab-
formed overlying the biopsy site. A retinectomy is lished, and cases with VRL with low interleukin
created that is large enough to allow the entrance ratios have also been reported [30]. Recently,
of the vitreous cutter and suction tubing. With gen- MYD88 mutations have been shown to occur fre-
tle cutting, several samples are obtained. Subretinal quently in VRL, and their detection may improve
aspirates should be placed in a mild cytofixative, the diagnostic yield of vitrectomy specimens [31].
such as herpes- glutamic acid buffer-mediated
organic solvent protection effect (HOPE) fixative
or CytoLyt (Cytyc) [23]. Central Nervous System
Approximately 97% of VRL cases are diffuse
large B-cell lymphoma (the remaining 3% are Cranial magnetic resonance imaging (MRI) with
T-cell and other rarer forms) with characteristic gadolinium is the diagnostic procedure of choice.
histologic and cytologic features [24]. Cells are Cranial lesions appear as multiple isointense
two to four times larger than normal lymphocytes nodules on T1-MRI and demonstrate characteris-
and pleomorphic and have scant cytoplasm. The tic dense and diffuse contrast enhancement
nuclei may be round, oval, or indented, with con- (Fig. 7.5). Meningeal enhancement with gado-
spicuous nuclear membranes, occasional finger- linium is indicative of meningeal involvement.
like protrusions, and multiple, prominent, CT scans of the chest, abdomen, and pelvis are
eccentrically located nucleoli (Fig. 7.4). Mitoses performed to exclude systemic involvement or
are frequently observed. With the use of electron systemic origin of the CNS involvement.
microscopy, intranuclear inclusions, cytoplasmic Cerebrospinal fluid sampling should be per-
crystalloids, and pseudopodal extensions of the formed in every patient with suspected or con-
cytoplasm, cytosomes, and autophagic vacuoles firmed PCNSL. Testicular ultrasound examination
can be identified [25]. is recommended in males over age 60 years
Due to limited cellularity, it can be difficult to because of frequent CNS involvement in testicu-
reach a conclusive diagnosis based solely on cyto- lar lymphoma.
pathologic findings. Ancillary techniques include Demonstration of malignant lymphocytes in
immunohistochemistry, flow cytometry, gene the CSF is confirmatory for the diagnosis of
rearrangement studies using the polymerase chain PCNSL. The CSF shows lymphocytic pleocyto-
reaction (PCR), and determination of interleukin sis, raised protein concentration, and normal or
levels. Immunohistochemistry can be used to low glucose concentration. Systemic nodal and/
identify markers for leukocytes (CD45), B cells or visceral involvement is rare at the initial diag-
(CD20, CD79a, PAX-5), T cells (CD45RO), and nosis but is not uncommon in the terminal stages.
macrophages (CD68) [26]. VRL frequently
expresses MUM1/IRF4, BCL6, and BCL2 and
typically lacks CD10 and plasma cell markers Differential Diagnosis
(such as Vs38c and CD138) [27]. The use of anti-
bodies directed against κ and λ light chains can be In general, all causes of chronic posterior uveitis
used to establish clonality [28]. PCR-based tests such as syphilis, sarcoidosis, tuberculosis, and
are used to detect monoclonal proliferation of B Whipple’s disease should be considered in the
lymphocytes, clonal heavy chain immunoglobulin differential diagnosis. Syphilitic uveitis is a late
gene rearrangement, bcl-2 gene translocation, and disease manifestation and may be preceded by
T-cell gene rearrangements. Flow cytometry pro- dermatologic signs (chancre or rash) and consti-
vides a means to quantitatively assess the propor- tutional flu-like symptoms. Ocular syphilis is
tion of cells in a given sample that demonstrate considered a CNS disease and requires systemic
Fig. 7.5 T1-weighted MRI of the brain with gadolinium roids (right). There is obvious CNS involvement in the
contrast, showing a diffusely enhancing area in the left cerebellum which underscores the importance of steroid
frontal lobe (a) T1-weighted MRI at the time of diagnosis avoidance at the time of initial staging (b). (a: Reprinted
of VRL (left) and 4 weeks following session of oral ste- from Singh et al. [32]. With permission from Elsevier)
therapy. Whipple’s disease is a rare, multi-organ toms include weight loss, diarrhea, polyarthralgia,
infection caused by the bacterium Tropheryma and abdominal pain, extraintestinal manifesta-
whipplei. Middle-aged Caucasian men in the tions including chronic uveitis can occur.
United States and continental Europe are most Definitive diagnosis is based upon PCR of vitre-
frequently affected [33]. While common symp- ous samples.
Vitreous amyloidosis can also mimic the clini- The sample displays metachromatic properties
cal appearance of VRL (Fig. 7.6). This rare entity under polarized light when stained with Congo
is usually observed in the setting of systemic red and toluidine blue, consistent with amyloido-
amyloidosis, although localized ocular involve- sis. Treatment in symptomatic patients consists
ment can occur. Vitreous involvement appears to of total vitrectomy in combination with phaco-
be linked to the hereditary neuropathies associ- emulsification and intraocular lens implantation.
ated with mutation of amyloid protein transthyre- Retinal lymphoma in the setting of adult T-cell
tin (TTR) [34]. Definitive diagnosis is made by leukemia/lymphoma (ATL) secondary to HTLV-1
vitreous biopsy. The specimen reveals an acellu- infection may present with retinal vasculitis, reti-
lar mix of fibrillar aggregates and focal rosettes. nal infiltration, and disc edema (Fig. 7.7). Retinal
a b
Fig. 7.6 Vitreous amyloidosis can mimic the clinical and overlying the posterior pole (a) and be observed as
appearance of vitreoretinal lymphoma. The vitreous depos- dense vitreous opacities on ultrasonography (b)
its are amorphous, predominantly in the posterior vitreous
a b
Fig. 7.7 The right optic disc, surrounding retina, and peri- from initial photographs, the perivascular infiltrates are
vascular areas show inflammatory infiltrates in a patient seen more distinctly (b). (Reprinted from Agarwal et al.
with HTLV-1 retinitis (a). Following vitrectomy 6 weeks [35]. With permission from Wolters Kluwer Health, Inc.)
biopsy with subsequent light microscopy evalua-

PVRL
tion, immunophenotypic studies, and PCR to
detect clonal T-cell receptor gene rearrangement
may be required for definitive diagnosis [36].
Choroidal tumors including metastasis and MRI of Head with
Lumbar Puncture
amelanotic melanoma can also mimic VRL. HIV Contrast
infection predisposes to both opportunistic infec-
tions and VRL; therefore, in an immunosup-
pressed patient, disseminated choroiditis due to
Nocardia chorioretinitis and Pneumocystis cho-
roiditis should be excluded. When the retina and CNS CNS
Positive Negative
the vitreous are involved, consideration must be
given to entities such as viral or fungal retinitis,
acute retinal necrosis syndrome, and toxoplas-
mosis. Multifocal subepithelial lesions of VRL
should be differentiated from diffuse unilateral HD-MTX
Based Regimen Ocular Radiotherapy
subacute neuroretinitis, birdshot retinocho-
roidopathy, multifocal choroiditis, multiple eva-
nescent white-dot syndrome, and punctate inner Ocular Radiotherapy Intravitreal MTX
choroidopathy. While intravascular lymphoma
can occur, when perivascular infiltrates are pres-
ent, conditions such as ocular sarcoidosis and WBRT
HD-MTX
Only for Relapse
retinal vascular disorders should be considered.
Patients with systemic lymphoma, not arising in Fig. 7.8 Schema outlining our current approach of man-
the CNS, develop choroidal rather than retinal agement of patients with VRL. HD-MTX, high-dose
infiltrates and are more likely to have a superim- methotrexate; WBRT, whole-brain radiation therapy
posed viral or fungal retinitis rather than an intra-
ocular lymphoma. expertise in lymphoma. As a high percentage of
patients with VRL eventually develop CNS dis-
ease, some experts recommend that the treatment
Treatment goal for VRL should be to eradicate ocular dis-
ease and prevent subsequent CNS involvement.
PCNSL is sensitive to corticosteroids; therefore, Others favor local therapy for disease confined to
exposure to corticosteroids should be avoided in the eye with close follow-up and systemic ther-
suspected cases until tissue diagnosis is con- apy if evidence of CNS disease develops. At pres-
firmed. The treatment of PCNSL has evolved in ent there is a lack of compelling evidence to
recent years, and there is a general consensus that suggest that ocular treatment prevents subsequent
regimens containing high-dose methotrexate development of CNS disease.
yield better response rates and outcomes than
regimens that do not contain high-dose metho- Local Therapy for VRL
trexate. A schema outlining an approach of man- Options for local treatment for VRL include
agement is shown (Fig. 7.8). intravitreal delivery of therapy and ocular radia-
tion. There has been no prospective, randomized
clinical trial that has compared these two thera-
Ophthalmic Treatment pies directly. At present, most experts prefer
intravitreal chemotherapy over ocular radiation
Management of VRL should ideally be under- as first-line therapy. Intravitreal methotrexate as
taken in partnership with an oncologist with primary therapy has been investigated with
a b
Fig. 7.9 Fundus appearance before (a) and after 3 months (induction and consolidation) of treatment with intravitreal
methotrexate (b). Note dramatic clearance of vitreous cells
encouraging results (Fig. 7.9; Table 7.1). In one may decrease the number of methotrexate injec-
study, 44 eyes (26 patients) were treated with tions and overall treatment-related side effects.
intravitreal methotrexate (400 μg/0.1 ml saline) More recently, there has been early evidence that
administered according to an induction-low-dose intravitreal melphalan (10 μg /0.1 ml
consolidation-maintenance regimen given over saline) may be suitable as first-line local therapy.
the course of 1 year [37]. Clinical remission was In a small series of three eyes with cytologically
achieved after a mean of 6.4 ± 3.4 (range, 2–16) confirmed VRL, a single intravitreal injection of
injections of methotrexate, and 95% of eyes melphalan achieved rapid tumor clearance from
required less than 13 injections to reach a com- the vitreous in two eyes, and tumor control was
plete response [37]. While intravitreal methotrex- achieved after six bimonthly injections in the
ate is fairly well tolerated, complications of third eye [39]. While further investigation is
therapy include corneal epitheliopathy, conjunc- needed, intravitreal melphalan may be a reason-
tival hyperemia, increased intraocular pressure, able treatment option and has the potential advan-
cataract, maculopathy, and rarely vitreous hem- tage of requiring fewer injections.
orrhage [37]. Rare instances of hypotony have Prior to the use of intravitreal therapy, external
been observed. Intravitreal rituximab alone or beam radiotherapy (EBRT) was widely used as
used in combination with methotrexate has also first-line treatment. Radiation remains an
shown encouraging results in smaller series. In important option, particularly for patients with
one study, 48 eyes (34 patients) were treated with advanced bilateral involvement, for those who
a median of 3.5 intravitreal injections of ritux- may not tolerate intravitreal chemotherapy, or for
imab (1 mg/0.1 ml saline) for new diagnosis of individuals who cannot return for multiple
VRL (68.8%), progressive disease (29.9%), and repeated injections. EBRT, or more recently
maintenance therapy (2.1%) [38]. Intravitreal intensity-modulated radiation therapy (IMRT), is
rituximab ± methotrexate was the sole treatment delivered with a dose range of 30–50 Gy, divided
in 19 (39.6%) of these eyes. A total of 31 eyes into small (1.5–2.0 Gy) fractions [40]. While
(64.6%) achieved a complete response (CR), fol- radiotherapy can achieve ocular control in the
lowing a median of 3 injections. Another 11 eyes majority of cases, there is no evidence to suggest
(22.9%) achieved partial response (PR). that its use prevents the development of CNS dis-
Recurrent disease developed in 7 eyes [38]. ease (Fig. 7.10). Due to the high incidence of
Using a combination approach with intravitreal bilateral disease, irradiation to both eyes should
methotrexate and rituximab is attractive, as it be considered for patients with biopsy-confirmed
a b
Fig. 7.10 Fundus photograph of the left eye demonstrat- nal beam radiotherapy at a total dose of 45 Gy (b).
ing multiple creamy subretinal pigment epithelial deposits (Reprinted from Agarwal et al. [35]. With permission
(a). Regression of the subretinal tumors following exter- from Wolters Kluwer Health, Inc.)
VRL. As whole-brain radiotherapy (WBRT) may sisting of intravenous methotrexate, vincristine,

have significant side effects, its use for prophy- and thiotepa as well as intrathecal methotrexate
laxis in patients without proven CNS involve- and cytarabine. Although a high initial response
ment is not advisable. Lenalidomide may be a was observed, the duration was limited, and addi-
reasonable alternative to radiation for relapsed or tional therapy was required due to relapse [44].
refractory cases [41, 42]. High-dose chemotherapy followed by stem-
cell transplantation has been studied in a limited
Systemic Therapy for VRL and Risk number of trials that have included small num-
of Subsequent CNS Disease bers of patients with ocular disease. These stud-
Disease relapse in the CNS is a major issue, par- ies have included both newly diagnosed patients
ticularly after local treatment with ocular radio- and patients with refractory or recurrent disease.
therapy or intravitreal chemotherapy. Systemic Although ocular response has been reported with
chemotherapy offers the potential advantage of this aggressive approach, high relapse rates along
simultaneous treatment of both ocular and micro- with observed toxicities associated with stem-cell
scopic intracranial diseases (Table 7.1). High- transplantation make this approach investiga-
dose methotrexate is most commonly used in the tional at the current time [45].
treatment in PCNSL. Batchelor and colleagues In a report of 221 immunocompetent patients
reported their experience in nine patients with with PCNSL and/or VRL, Grimm and colleagues
intraocular lymphoma treated with intravenous reported no difference in disease progression
high-dose methotrexate at a concentration of 8 g/ rates or overall survival in patients treated with
m2 [43]. Potentially cytotoxic, micromolar levels local therapy versus those who received systemic
of methotrexate were detectable in the aqueous therapies. This series, although the largest to
and vitreous humor in most patients. An intra- date, was an uncontrolled, multicenter, and retro-
ocular response was reported in seven patients, spective study that utilized different treatments
with CR in six and PR in one. Unlike PCNSL, depending on the preference of the treating phy-
experience with combination chemotherapy in sician [46]. It is possible that a combination of
VRL is extremely limited. Sandor and colleagues intravitreal and systemic chemotherapy may pro-
reported 100% response rate (11 CRs, 3 PRs) long the time to relapse [47].
in 14 patients (5 with intraocular involvement) A recent multicenter European study
treated with a complex treatment regimen con- reported on outcomes of 78 patients treated at
17 centers based upon physician preference. Central Nervous System

Patients received ocular radiotherapy and/or
ocular chemotherapy (31 patients), extensive In the past, WBRT was the mainstay of treatment
systemic treatment (21 patients), and a combi- for PCNSL. This resulted in improvement in
nation of ocular and extensive systemic treat- median survival to 12–18 months, compared to
ment (23 patients); 3 patients did not receive 4 months for untreated individuals [49]. In the
treatment. Extensive therapy included various 1990s, clinical trials using a combination of
combinations of systemic and intrathecal che- methotrexate-based chemotherapy and radiother-
motherapy, whole- brain radiotherapy, and apy reported a further improved median survival
peripheral blood stem- cell transplantation. of 40 months [49]. The combination of WBRT
Overall, there was no difference at the rates of and chemotherapy is associated with a significant
development of CNS disease (absent initially) risk of neurotoxicity in older individuals (demen-
between treatment groups (36% at a median tia); therefore chemotherapy alone is frequently
follow-up of 49 months). selected over WBRT for individuals over age
At the present time, there is a lack of compel- 60 years. More recently, reduced dose WBRT
ling evidence that systemic chemotherapy will (23.4 Gy) has been combined with chemotherapy
prevent the development of CNS disease. resulting in minimal neurotoxicity [50].
Moreover, its use has been associated with more Gamma Knife radiosurgery (GKRS) has
severe adverse effects compared with local treat- been studied in a prospective, observational
ment [48]. An individualized patient-specific cohort of 128 patients with histologically con-
approach is generally recommended (Box 7.1). firmed PCNSL. Patients were treated with
either methotrexate (dose of 8 g/m2) alone
(control, 73 patients), or they received metho-
Box 7.1 Salient features of Primary trexate plus GKRS (dose of 11–16 Gy, median
Central Nervous System Lymphoma 11 Gy) (55 patients). After a follow-up period
of 24–49 months (mean, 36.9 months), the
median survival rate from initial diagnosis was
• External beam radiotherapy alone or 26.8 months in the chemotherapy group and
combined with systemic chemotherapy 47.6 in the chemotherapy, plus GKRS, group
has been used in treatment of PVRL. (p-value, 0.0034). All lesions treated with GKRS
• Side effects include radiation retinopa- demonstrated a complete response based on MRI
thy, radiation maculopathy, and there is 3–8 weeks (mean range, 6.3 weeks) following
risk of recurrence of VRL and PCNSL. therapy [51].
• Treatment options that include intravitreal As the blood-brain barrier restricts drug
chemotherapy using methotrexate and/or entry into the CNS, various strategies to over-
rituximab are increasingly been employed come this have been evaluated. These include
in controlling the VRL and avoid the side the use of high-dose chemotherapy, intrathe-
effects of EBRT. Major vision-threatening cal drug delivery, intraventricular drug delivery
side effects have not been reported with by a reservoir, and temporary disruption of the
intravitreal chemotherapy. blood-brain barrier (BBBD) with mannitol infu-
• Methotrexate-containing multiagent sion [49]. In a large multi-institutional experi-
chemotherapy regimens are the pre- ence of 149 newly diagnosed PCNSL patients
ferred therapy for treatment of central (with no prior WBRT) who were treated with
nervous system disease. The timing and osmotic BBBD and intra-arterial (IA) methotrex-
dose of whole-brain radiotherapy is ate, an overall response rate of 82% (58% CR;
unclear, given the significant risks of 24% PR) was reported with a median progres-
late neurotoxic effects. sion-free survival and overall survival of 1.8 and
3.1 years, respectively [52]. Maculopathy is an
a b
c d
Fig. 7.11 Color photographs of left fundus from two completion of treatment (b). Note progression of retinal
patients with primary central nervous system lymphoma pigment epithelium changes (c). Optical coherence
treated with blood-brain barrier disruption therapy dem- tomography showing irregular thickening of the retinal
onstrating the spectrum of hyperpigmentation and retinal pigment epithelium (d). (Reprinted from Galor et al. [53].
pigment epithelium (RPE) loss within the macula. Mild With permission from Elsevier)
and moderate severity (a). Second patient 4 months after
ocular complication associated with BBBD with commonly adopted as the preferred treatment
mannitol (Fig. 7.11). The characteristic findings option for this disease entity. The decision to use
include RPE clumping in the macula and hyper- WBRT and its timing and dose are still unclear,
pigmentation in the foveal region associated with given the significant risks of late neurotoxic effects.
variable RPE atrophy. Mannitol maculopathy is Further evaluation is needed to investigate the role
typically bilateral but often asymmetric. Unlike of radiation in upfront treatment of PCNSL.
age-related wet macular degeneration, there is For recurrent or refractory PCNSL, small mol-
an absence of subretinal fluid or macular edema. ecules have recently been investigated. Bruton’s
The maculopathy may progress, even after com- tyrosine kinase (BTK) inhibitor, ibrutinib, has
pletion of treatment. been studied at doses of 560 mg and 840 mg
In recent years, high-dose methotrexate- daily. In the 560 mg trial, 52 patients with recur-
containing multiagent regimens have been rent PCNSL or ocular lymphoma were enrolled
in a French study, and the overall response rate Summary

(ORR) was 50% after two cycles of ibrutinib [54].
In the 840 mg trial, 20 patients with recurrent Primary central nervous system lymphoma
PCNSL and secondary CNS lymphoma achieved (PCNSL) is a variant of extra-nodal non-
an ORR of 75% [55]. Immune checkpoint inhibi- Hodgkin’s lymphoma (NHL), a high-grade
tors have also recently been investigated. In a malignancy predominantly of B-cell origin.
recent series of five patients (four with relapsed/ There are no known risk factors in immunocom-
refractory PCNSL and one with CNS relapse of petent individuals; however, congenital immuno-
primary testicular lymphoma), the anti-PD1 anti- deficiency and iatrogenic and acquired
body nivolumab resulted in a 100% clinical and immunosuppression (HIV/AIDS) are risk factors
radiographic response. Of these, three patients for PCNSL. The brain, spinal cord, leptomenin-
had progression-free survival at 13–17 months ges, and eyes, either separately or in combina-
which suggested that nivolumab may be useful tion, can be involved. Patients may be
in the treatment of relapsed/refractory PCNSL asymptomatic, but up to 50% present with pain-
[56]. This initial small study resulted in a subse- less blurred vision, floaters, or both. The hall-
quent multicenter trial to investigate single-agent mark diagnostic features are vitreous cells and
nivolumab in PCNSL and testicular lymphoma subretinal pigment epithelial infiltrates.
(NCT02857426). In addition, a single-institution Diagnostic techniques including vitreous, retinal,
trial with pembrolizumab (NCT02779101) is and subretinal biopsy are needed to establish
ongoing to investigate the role of PD-1 blockade diagnosis in most cases. There is a general con-
in PCNSL. sensus that regimens containing high-dose meth-
otrexate (at least 3.5 G/m2), with or without
WBRT, yield better response rates than regimens
Prognosis that do not contain high-dose methotrexate.
Disease relapse in the CNS is a major issue, par-
Survival of patients with PCNSL following ticularly after local treatment with intravitreal
WBRT is poor, ranging from 12 to 18 months, therapy and/or radiation. Management should
but may increase following high-dose ideally be undertaken in partnership with an
methotrexate-based chemotherapy alone or when oncologist with expertise in lymphoma.
used in combination with radiation [57]. Age less
than 60 years at diagnosis and high initial perfor-
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Retinal Metastatic Tumors
8
Peter H. Tang, Lejla Vajzovic,
and Prithvi Mruthyunjaya
Introduction mary malignancies which develop RM are cuta-

neous melanoma, pulmonary carcinoma, breast
Metastatic tumors to the eye are the most common adenocarcinoma, gastrointestinal carcinoma, and
intraocular malignancy. The usual primary sites uterine adenocarcinoma.
are lungs in men and breasts in women [1]. In
most cases, intraocular metastasis is limited to
the choroid; however, other ocular structures Pathophysiology
such as the vitreous, optic nerve, iris, and, rarely,
the retina may be involved. For tumors to metastasize to other regions of the
Retinal metastasis was first described in 1879 body, such as the eye, they must dissociate from
by Schiess-Gemuseus and Roth in a patient with the primary tumor, transgress the basement mem-
primary cutaneous melanoma [2]. In 2012, brane, and intravasate into the systemic hemato-
Srivastava and Bergstrom reviewed 37 reported logic and lymphatic circulation [47–50]. These
cases of retinal metastasis (RM) and noted that processes are initiated by a complex series of cel-
the most common primary sites were cutaneous lular changes called epithelial-to-mesenchymal
melanoma, pulmonary carcinoma, and gastroin- transition (EMT) [51, 52]. EMT allows cancer
testinal adenocarcinoma [3]. cells to gain migratory capabilities through
We identified 42 reported cases of RM, either changes in the expression of binding proteins
confined to the retina or also involving the vit- such as cadherins and integrins as well as through
reous, published in the English literature from production of proteolytic enzymes that degrade
1935 to 2017 (Table 8.1). Most cases present uni- the extracellular matrix to facilitate invasion
laterally. The right (OD) and left (OS) eyes are through surrounding connective tissue [47, 48,
involved equally. In most cases, there is a known 50, 52–54]. EMT has also been shown to activate
history of primary non-ocular malignancy at the the TGFβ pathway to transform cancer cells to a
time of RM diagnosis. The most common pri- stem cell-like state, which endows them with the
capacity to self-renew and differentiate, contrib-
P. H. Tang · P. Mruthyunjaya (*) uting to metastasis [55–57].
Department of Ophthalmology, Byers Eye Institute, Metastatic cells gain access to the eye
Stanford University School of Medicine, Palo Alto, hematogenously. The intraocular location of

CA, USA metastases depends on several factors, such as
vascular circulation patterns and molecular fac-
L. Vajzovic tors that promote growth within specific tissue
Duke University Eye Center, Durham, NC, USA

102 P. H. Tang et al.
Table 8.1 Review of clinical findings in patients with retinal metastasis

Primary tumor (if
known at time of Specimen for Survival
Author(s) Age Sex eye symptoms) Signs histopathology Histopathology (months)
Smoleroff 55 M Gastroesophageal White, elevated, Autopsy Tumor cell 1
and adenocarcinoma irregular mass in invading primarily
Agatston (yes) inferotemporal retina retina and
(1934) [4] with dilated, tortuous subretinal space
veins and a few
scattered hemorrhages
Uhler 26 M Cutaneous Infiltration of temporal Autopsy Spindle-shaped NS
(1940) [2] melanoma (yes) retina malignant cells
Kennedy 51 M Rectosigmoid Sharply circumscribed Enucleation Atypical 9
et al. adenocarcinoma grayish-white lesion in pseudostratified
(1958) [5] (no) macula columnar cells
Duke and 60 F Uterine White elevated mass in Enucleation Cuboidal/ 6
Walsh adenocarcinoma macula with overlying columnar
(1959) [6] (yes) vitreous opacities pleomorphic cell
sheets covering
angle, iris,
vitreous, retinal,
and optic nerve
surface
Liddicoat 43 M Cutaneous Small retinal Autopsy Epithelioid tumor 2 weeks
et al. melanoma (yes) hemorrhage and cells invading
(1959) [7] perivascular white inner retinal
sheathing in temporal layers only
retinal midperiphery
Riffenburgh 45 M Cutaneous Vitreous cells, irregular Enucleation Metastatic NS (alive
(1961) [8] melanoma (yes) vascularized gray mass malignant 5 years
with sharp borders and melanoma in the later)
overlying hemorrhage retina only
in nasal retina
Koenig 56 M Undifferentiated Vitreous floaters; white Enucleation Undifferentiated 13
et al. bronchogenic lesion with soft carcinoma cells
(1963) [9] pulmonary exudative edges and involving retina
carcinoma (no) neovascularization in with focal
temporal retina; invasion into
considerable exudation choroid
and subretinal fluid was
present
Flindall 68 M Unknown (no) Dense vitreous exudate Enucleation Anaplastic tumor NS (alive
and overlying the disk and cells of epithelial 2 years
Fleming veillike exudate origin invading later)
(1967) [10] inferiorly mainly inner
retina, but also
vitreous and optic
nerve head
Klein et al. 52 M Squamous cell Yellow-white infiltrate Autopsy Carcinoma cells 3
(1977) [11] pulmonary temporal to macula in similar to primary
carcinoma (yes) OD tumor invading
retina only in OD
Yellow-white infiltrate Carcinoma cells
superior and invading retina,
inferotemporal to the optic nerve, and
disk; inferior choroid in OS
exudative retinal
detachment in OS
8 Retinal Metastatic Tumors 103
Table 8.1 (continued)
Primary tumor (if
Young 63 M Pulmonary Vitreous cells; white Vitreous Adenocarcinoma 7
et al. carcinoma (yes) retinal macular mass biopsy, then cells;
(1979) [12] with surface autopsy morphological
hemorrhages; changes related to
perivascular white EBRT, but few
infiltrates vitreous tumor
cells seen
Robertson 43 F Cutaneous Brown plaque over and 4
et al. melanoma (yes) involving superior retina
(1981) [13] in OD
Golden-brown vitreous Vitreous Malignant
spherules; brown plaque biopsy in OS pigmented,
over and involving pleomorphic
superior retina in OS melanoma cells in
OS
37 F Cutaneous Golden-brown vitreous Aqueous Heavily NS (alive
melanoma (yes) spherules subsequently biopsy, then pigmented, highly 11 months
infiltrating anterior enucleation malignant later)
chamber with increased epithelioid cells
IOP in OD disseminated
throughout
anterior chamber,
vitreous, and
surface retina
Piro et al. 56 F Breast infiltrative Vitreous opacities in Postmortem Breast carcinoma 5
(1982) [14] ductal carcinoma OD enucleation in cells in the
(yes); cerebral OD vitreous and retina
malignant in OD
astrocytoma (yes)
White vitreous opacities PPV, then Breast carcinoma;
in OS postmortem tumor cells
enucleation in infiltrating vitreous,
OS retina, and inner
surface of ciliary
body in OS
Letson and 44 M Cutaneous Superficial gray-brown None 3
Davidorf melanoma (yes) retinal and perivascular
(1982) [15] infiltrates with feathery
edges in OD
Superficial gray-brown None
retinal and perivascular
infiltrates with feathery
edges in OS; brown
choroidal lesion inferior
to disk
de Bustros 33 M Cutaneous Tan retinal mass NS 5.5
et al. melanoma (yes)
(1985) [16]
Takagi 45 M Pulmonary Whitish vitreous Enucleation Adenocarcinoma 3
et al. adenocarcinoma opacities; white masses (prevention of cell nests found in
(1989) [17] (yes) involving disk and CNS spread) inner retina, optic
inferotemporal retina; nerve head, and
white exudate-like vitreous; tumor
lesions with hemorrhages emboli within
along retinal vessels central retinal vein
(continued)
Primary tumor (if
Best et al. 71 F Cutaneous Thick yellow-white PPV, then Large pigmented NS
(1990) [18] melanoma (yes) globular vitreous enucleation pleomorphic
opacities melanoma cells;
melanoma cells
infiltrating retina,
optic nerve head,
vitreous (also
orbital tissue
adjacent to PPV
wound)
Leys et al. 49 M Oat cell White retinal plaque Autopsy Retinal tumor 1
(1990) [19] pulmonary temporal to macula cells
carcinoma (yes) corresponding to
the original oat
cell carcinoma
42 F Breast Vitreous opacities over PPV Epithelioid 18
adenocarcinoma the macula malignant cells
(yes)
Balestrazzi 40 F Cutaneous Vitreous hemorrhage; Transscleral Retinal pigmented 17
et al. melanoma (yes) yellow-white resection melanoma cells (suicide)
(1995) [20] vascularized mass in
superonasal retina with
vitreous condensation
and pigment dusting
Spraul 74 F Adenocarcinoma Yellow-white, solid Enucleation Adenocarcinoma NS (alive
et al. of the breast or retinal tumor in the tumor cells 10 months
(1995) [21] colon (yes) superotemporal involving retina later)
quadrant associated
with shallow serous
retinal detachment
Spraul 55 M Cutaneous Vitreous hemorrhage, PPV, then Pleomorphic NS
et al. melanoma (yes) pigmented mass in enucleation pigmented cells; (several
(1996) [22] temporal retina melanoma cells months)
invading retina
and vitreous
67 F Cutaneous Vitreous cells, yellowish PPV with Pleomorphic NS (alive
melanoma (yes) subretinal infiltrates subretinal pigmented cells 24 months
aspirate with cytologic later)
features identical
to cutaneous
melanoma cells
Gunduz 81 M Cutaneous Total hyphema, no PPV, then Nonpigmented 26
et al. melanoma (yes) posterior view enucleation pleomorphic
(1998) [23] melanoma cells;
amelanotic
melanoma
infiltrating retina
and vitreous;
extrascleral
seeding through
the filtering
implant
Primary tumor (if
58 M Cutaneous Clumps and sheets of Vitreous Pigmented 12
melanoma (yes) pigmented vitreous cells biopsy pleomorphic
(FNAB) melanoma cells
36 M Cutaneous Clumps and sheets of PPV Nonpigmented 3
melanoma (yes) nonpigmented vitreous pleomorphic
cells, no view of fundus melanoma cells
Clumps and sheets of
nonpigmented vitreous
cells, ill-defined retinal
whitening at ora serrata
Spadea 40 F Cutaneous Vitreous pigment; Transscleral Epithelioid 12
et al. melanoma (yes) yellow-white resection pigmented (suicide)
(1998) [24] vascularized lesion in melanoma cells
the superior peripheral
retina
Hutchison 63 F Large bowel Pale, elevated, vascular None NS (alive
et al. adenocarcinoma lesion superotemporal 3 months
(2001) [25] (yes) to the macula with later)
associated serous retinal
detachment involving
the macula
Soheilian 49 M Cutaneous Mild vitreous PPV in OD Pigmented 12
et al. melanoma (yes) hemorrhage mixed with pleomorphic
(2002) [26] large nonpigmented melanoma cells in
cells; pigmented mass OD
in superotemporal retina
in OD
Dense vitreous PPV × 2 in Initial negative
hemorrhage mixed with OS then pigmented
large nonpigmented pleomorphic
cells in OS melanoma cells in
OS
Truong 59 F Breast Milky, white intraretinal None Unknown
et al. adenocarcinoma and subretinal fungating
(2002) [27] (yes) mass involving the
temporal juxtafoveal
macula associated with
a shallow serous retinal
detachment
Zografos 48 M Cutaneous Beige-colored vitreous PPV NS NS (alive
et al. melanoma (yes) cell aggregates 3 months
(2003) [28] later)
Zografos 57 F Suspected Pale beige spherical None NS (alive
et al. primary vitreous mass over 11 months
(2004) [29] pulmonary grayish-beige retinal later)
melanoma (yes) mass; preretinal
hemorrhage
Saornil 70 M Gastric Yellow-white solid Enucleation Pleomorphic 23
et al. adenocarcinoma retinal juxtapapillary signet ring cells
(2004) [30] (yes) mass
(continued)
Primary tumor (if
Rossi et al. 41 M Non-small cell White-elevated mass None 3
(2005) [31] lung cancer (yes) lesions with serous
retinal detachment in
superonasal and
temporal macula in OD
White-elevated mass None
lesion with serous
retinal detachment in
superotemporal macula
in OS
Apte et al. 39 M Adenocarcinoma Intraretinal and PPV, Tall, NS (alive
(2005) [32] of the cecum subretinal hemorrhage endoresection hyperchromatic, 3 months
(yes) along inferotemporal pleomorphic, later)
arcade mucin-containing
cells arranged in
an adenomatous
papillary pattern
and invading
retina only
Sirimaharaj 60 F Breast Vitreous cells; white PPV Malignant cells 8
et al. adenocarcinoma precipitates and consistent with
(2006) [33] (yes) hemorrhagic spots of adenocarcinoma
nasal midperipheral
retina and sheathing
along the nasal retinal
vessels
Rundle and 55 F Breast Well-circumscribed, None NS (alive
Rennie adenocarcinoma solitary, vascular, white 2 months
(2006) [34] (yes) retinal lesion temporal later)
to the fovea with
subretinal fluid
Khurana 76 M Cutaneous Anterior chamber and PPV Pigmented 6
et al. melanoma (no) vitreous pigmented epithelioid and
(2007) [35] cells; preretinal spindle melanoma
pigmentation along cells
vascular arcades in the
posterior pole and
periphery
Alegret 15 M Nasopharyngeal Amelanotic infiltration None NS
et al. carcinoma (yes) in the retina along
(2009) [36] inferotemporal arcade
Kim et al. 64 F Gastric Flat, whitish macular Vitreous Spherical clusters NS (alive
(2010) [37] adenocarcinoma infiltrations with white biopsy in OD of tumor cells 1 month
(yes) to yellow vitreous seeds with formation of later)
in OD a gland-like
empty plural
spaces in OD
Flat, whitish macular
infiltrations with white
to yellow vitreous seeds
in OS
Primary tumor (if
Coassin 54 F Small-cell lung Vitreous cell, whitish PPV, retinal Small round NS (alive
et al. cancer (yes) retinal infiltrated with biopsy neoplastic cells 7 months
(2011) [38] irregular margins, see on vitreous later)
intraretinal cytology (retinal
hemorrhages, biopsy tissue lost)
telangiectatic blood
vessels and hard
exudates in temporal
macula
Payne et al. 62 M Small-cell lung Vitreous haze, retinal Vitreous No neoplastic NS (alive
(2012) [39] cancer (yes) whitening in the biopsy, then cells; sheets of 10 months
temporal macula and PPV, retinal adenocarcinoma later)
midperiphery associated biopsy cells
with preretinal
hemorrhages
Shields 64 F Lung carcinoma White retinal mass with FNAB Malignant cells NS (alive
et al. (yes) intrinsic vascularity and 4 months
(2014) [40] vitreous hemorrhage later)
45 M Malignant Vitreous seeds, retinal Enucleation NS (alive
melanoma (yes) whitening 17 months
later)
59 M Malignant Subretinal fluid, retinal Enucleation 1 month
melanoma (yes) whitening
85 F Malignant Vitreous seeds, vitreous Enucleation 1 month
melanoma (yes) hemorrhage, retinal
whitening
56 F Esophageal Retinal whitening, None 1 month
carcinoma (yes) subretinal fluid
58 F Breast carcinoma Retinal whitening, None 1 month
(yes) subretinal fluid
55 F Malignant Retinal whitening None 1 month
melanoma (yes)
75 F Breast carcinoma Yellow retinal mass None NS
(yes) with intrinsic
hemorrhage and
surrounding exudation
Taubenslag 75 M Unknown (no) Yellow-white retinal PPV Malignant cells NS (alive
et al. lesion with scattered 18 months
(2015) [41] hemorrhages, vitreous later)
cell
Ishida et al. 68 F Breast Retinal whitening, None Unknown
(2017) [42] adenocarcinoma peripapillary brown
(yes) pigmentation, serous
retinal detachment
65 F Lung High dome-shaped None NS (alive
adenocarcinoma subretinal lesion, retinal 3 years
(yes) hemorrhages, subretinal later)
fluid, vitreous
hemorrhage
Essadi I 62 M Clear cell renal Retinal whitening with None NS (alive
et al. carcinoma (yes) hemorrhage 4 months
(2017) [43] later)
(continued)
Primary tumor (if
Correa de 61 F Breast Retinal whitening with PPV Neoplastic cells NS
Mello et al. adenocarcinoma intrinsic vessels
(2017) [44] (yes)
Gokmen 11 F Anaplastic Yellow retinal lesions None 12
et al. astrocytoma (yes) along optic disc
(2017) [45]
Praidou 70 M Hepatocholangio- Single whitish elevated PPV Neoplastic cells 12
et al. carcinoma (yes) retinal lesion along
(2017) [46] inferior-temporal
arcade, vitreous
infiltration, subretinal
fluid
FNAB fine needle aspiration biopsy, PPV pars plana vitrectomy, NS not stated, OD ocular dexter, OS ocular sinister, IOP
intraocular pressure
types [47, 48, 58]. Metastases occur in the cho- changes may suggest an infectious necrotizing
roid commonly than in the retina because the retinitis caused by cytomegalovirus, herpetic
posterior uvea is more vascular [59, 60]. The size viruses, toxoplasmosis, or other etiologies [39].
of tumor emboli may also play a role [61]. On In contrast to choroidal metastasis, RM often
reaching the secondary site within the eye, tumor presents with overlying cellular vitreous infiltra-
cells undergo a reversal process termed mesen- tion and may masquerade as an intermediate uve-
chymal-to-epithelial transition so that they regain itis [26]. Metastasis from cutaneous melanoma
phenotypic and genotypic properties of the pri- can present as large, golden-brown spherules in
mary tissue [62–64]. the vitreous [13, 65, 66]. These differ from other
forms of metastatic carcinoma that usually pres-
ent as nonpigmented vitreous opacities [14].
Clinical Features Irrespective of pigmentation, cellular aggregates
within the vitreous in the form of spherules
Presenting symptoms typically include decreased should alert the clinician to the possibility of a
vision (ranging from 20/20 to light perception), neoplastic rather than inflammatory etiology.
floaters, and eye pain. In general, clinical symp- Glaucoma secondary to the obstruction of aque-
toms reflect the size and location of the metasta- ous outflow by the accumulation of tumor cells in
ses as well as vitreous involvement and retinal the trabecular meshwork has been described as
detachment (RD). an additional feature of RM. RD is an uncommon
Retinal metastases most commonly present as presenting sign of retinal metastases.
focal yellow-white, intraretinal patches. They are
almost always unilateral and solitary; however,
bilateral and multifocal presentation has been Diagnostic Evaluation
reported (Fig. 8.1). The ophthalmoscopic appear-
ance of RM may resemble a retinal infarct, since Clinical examination along with fundus photog-
perivascular tumor infiltration can cause retinal raphy and fluorescein angiography may enable
opacification along with associated intraretinal differentiation of RM from retinal vasculitis or
hemorrhages and subretinal exudates. As the other vascular occlusive diseases. Optical coher-
tumor grows, intraretinal opacification becomes ence tomography (OCT) has been used to charac-
more extensive. Coalescing patches of retinal terize intraocular tumors, but its precise role in
whitening associated with retinal vascular diagnosing RM has yet be established [67].
Confirmatory diagnosis of a RM by biopsy In conjunction with an oncologist, systemic

may be beneficial to the patient in several ways. work-up for a primary tumor is recommended in
First, it assists in differentiating metastasis from all patients presenting with ocular features sug-
inflammatory conditions having similar clinical gestive of a RM.
features. Second, the cell type identified in the
biopsy specimen may indicate the type of cancer
and the likely site of origin. Third, biopsy may Differential Diagnosis
help guide therapy, for both the primary tumor
and the ocular metastasis. Before 1979, most Conditions most likely to mimic RM include reti-
cases of RM were diagnosed at autopsy or after nal infections and inflammatory retinitis, vaso-
enucleation [3]. occlusive retinal disorders, choroidal metastasis
Biopsy is being performed more widely to with secondary retinal infiltration, and disorders
enhance diagnosis. Vitreous infiltrates are sam- with vitreous opacities such as intermediate uve-
pled by pars plana vitrectomy (PPV), whereas itis, amyloidosis, and retinal lymphoma.
chorioretinal biopsy is performed when there is
no vitreous infiltration. In 1988, Eagle reported a
case of carcinomatous retinitis which had been Treatment (Surgical,
diagnosed by vitreous aspirate and eye wall Chemotherapy, and Radiotherapy)
biopsy [68]. In 1995, Balestrazzi et al. described
local resection of a retinal metastasis from pri- Treatment of RM is ideally administered by a
mary cutaneous melanoma [20], and Spadea multidisciplinary team involving ophthalmology,
et al. later described the technique for chorioreti- hematology/oncology, radiation oncology, and
nal biopsy using a transscleral approach [24]. the patient’s primary care physician. It is influ-
More recently, Payne et al. described an enced by several factors including the nature of
endoresection technique for retinal biopsy of the primary tumor, extent of systemic metastases,
metastases from small-cell lung cancer using prior therapy, and the overall functional status of
PPV, subretinal fluid injection, diathermy, biman- the patient.
ual retinectomy, air fluid exchange, laser, and Over the past 25 years, patients with RM have
long-acting gas tamponade. The biopsy site for most often been treated with palliative, hyper-
this procedure was chosen peripherally and at the fractionated external beam radiotherapy (EBRT).
junction of normal and abnormal retina to mini- Stereotactic radiosurgery, also known as gamma
mize visual sequelae and to improve histopatho- knife radiosurgery (GKR), has also been shown
logic evaluation of active disease at the tumor to be effective in treating ocular malignancies
margin [39]. [70–72]. Enucleation is reserved for those with
PPV is currently the preferred technique for intractable pain. Small groups of patients are
obtaining vitreous cells for cytologic evaluation. treated with systemic chemotherapy alone or in
It is crucial to have an experienced cytopatholo- combination with EBRT or local subconjunctival
gist interpret the minute quantity of tissue that is chemotherapy (Table 8.1). Resection of the RM
obtained. Immunohistochemical stains aid inter- lesion is reserved for patients with solitary,
pretation of the cytology specimen [22, 69]. A peripheral lesions and may be combined with
negative result does not necessarily rule out systemic chemotherapy and EBRT [20, 24, 32].
metastasis, especially when only the retina is There is a single report of successful verteporfin
involved [14]. If clinical suspicion is high, even photodynamic therapy (PDT) of a well-circum-
in light of a negative diagnostic PPV, a chorioreti- scribed, vascularized tumor in the macula thought
nal biopsy may be needed to establish a diagnosis to be a RM from breast adenocarcinoma [34].
(Fig. 8.1) [38, 39]. We do not routinely recom- However, in a recently reported case of vitreous
mend fine needle aspiration when there is no metastasis from melanoma, the metastasis was
mass lesion. not effectively treated by systemic immune mod-
a b
c d
e f
Fig. 8.1 A 78-year-old Caucasian male with a past medical (1200 mcg/0.05 mL) and started on IV acyclovir. Intravitreal
history of recurrent, small-cell lung cancer (SCLC) pre- CMV, HSV, and VZV PCR assays were negative. Serum
sented for evaluation for new-onset floaters and blurred assays for HSV and CMV were also negative. The serum
vision in the right eye 10 days after the second cycle of che- VZV IgG was positive (consistent with immunity to VZV).
motherapy. Anterior segment examination of both eyes and Despite antiviral therapy, the retinitis progressed (b). Retinal
fundus examination of the left eye were unremarkable. The biopsy subsequently revealed small-cell carcinoma involving
right eye showed a mild cellular vitreous infiltrate and the retina (c). The tumor cells showed the typical nuclear
numerous, patchy, white, retinal infiltrates with associated molding of small-cell carcinoma (d). Immunoperoxidase
retinal hemorrhages (a). In this immunocompromised stains were confirmatory with positive staining for EMA (e)
patient, the presentation was concerning for viral retinitis. and TTF-1 (f). (Courtesy of Rishi Singh MD, Peter Kaiser
The patient was given intravitreal foscarnet in October 2009 MD, and Nathan Steinle MD, Cleveland, Ohio)
ulator such as pembrolizumab [73]. Palliative vit- 11. Klein R, Nicholson DH, Luxenberg MN. Retinal

metastasis from squamous cell carcinoma of the lung.
rectomy may be effective [74]. Am J Ophthalmol. 1977;83(3):358–61.
12. Young SE, Cruciger M, Lukeman J. Metastatic car-
cinoma to the retina: case report. Ophthalmology.
Prognosis 1979;86(7):1350–4.
13. Robertson DM, Wilkinson CP, Murray JL, et al.

Metastatic tumor to the retina and vitreous cav-
The posttreatment visual acuity ranges from ity from primary melanoma of the skin: treatment
20/20 to no light perception (Table 8.1). Systemic with systemic and subconjunctival chemotherapy.
prognosis is guarded with an average survival of Ophthalmology. 1981;88(12):1296–301.
14. Piro P, Pappas HR, Erozan YS, et al. Diagnostic vit-
10 months (range 2 weeks to 5 years) following rectomy in metastatic breast carcinoma in the vitre-
diagnosis of the RM. ous. Retina. 1982;2(3):182–8.
15. Letson AD, Davidorf FH. Bilateral retinal metas-

tases from cutaneous malignant melanoma. Arch
Ophthalmol. 1982;100(4):605–7.
Conclusions 16. de-Bustros S, Augsburger JJ, Shields JA, et al.

Intraocular metastases from cutaneous malig-
Retinal metastases are rare. The differential diag- nant melanoma. Arch Ophthalmol. 1985;103(7):
nosis includes retinal vasculitis and vascular 937–40.
17. Takagi T, Yamaguchi T, Mizoguchi T, et al. A

occlusion. Biopsy is useful in confirming the case of metastatic optic nerve head and retinal car-
diagnosis and may indicate the site of the primary cinoma with vitreous seeds. Ophthalmologica.
tumor when this is not known. Treatment usually 1989;199(2–3):123–6.
involves some form of radiotherapy. The man- 18. Best SJ, Taylor W, Allen JP. Metastatic cutaneous
malignant melanoma of the vitreous and retina. Aust
agement of the patient is best undertaken by a N Z J Ophthalmol. 1990;18(4):397–400.
multidisciplinary team. The life expectancy of 19. Leys AM, Van-Eyck LM, Nuttin BJ, et al. Metastatic
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108(10):1448–52.
20. Balestrazzi E, Blasi MA, Marullo M, et al. Local exci-
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Neuro-oculocutaneous Syndromes
(Phakomatoses)
9
Elaine Binkley, Elias I. Traboulsi, and Arun D. Singh
The term phakomatosis is derived from the Greek The principal systemic manifestations of the
word phakoma, which means “birth mark.” In phakomatoses are due to the development of
1923, van der Hoeve grouped together von Hippel- hamartomas, which are benign tumors arising
Lindau disease, tuberous sclerosis, and neurofi- from tissues normally present in the organ in
bromatosis because of their manifestations at which they arise (Box 9.1). Patients with most
birth, autosomal-dominant inheritance, and phakomatoses are also predisposed to cancer and
involvement of multiple systems [1]. Subsequently, have a decreased life span. Advances in molecu-
encephalofacial angiomatosis (Sturge-Weber syn- lar genetics have led to the identification of genes
drome) was added, although there have been no responsible for von Hippel-Lindau disease,
instances of clear-cut inheritance of this condition. tuberous sclerosis, and neurofibromatosis and
Other common features of the phakomatoses have allowed molecular genetic diagnosis
include a predominance of neural and ocular (Table 9.2).
involvement with variable cutaneous and visceral
manifestations (Table 9.1). Wyburn-Mason syn-
drome, retinal cavernous hemangioma, and ataxia ox 9.1 Characteristic Features
B
telangiectasia have also been grouped with the of the Phakomatoses
phakomatoses and have been included in this
chapter. Phakomatosis pigmentovascularis and
neurocutaneous melanosis are briefly described. • Neuro-oculocutaneous syndromes
• Systemic hamartomatoses
E. Binkley • Familial predisposition to cancer
Department of Ophthalmology, Cole Eye Institute
• Autosomal-dominant inheritance
(i32), Cleveland Clinic Foundation,
Cleveland, OH, USA (exceptions)
E. I. Traboulsi
Department of Pediatric Ophthalmology and
Strabismus, Center for Genetic Eye Diseases, Cole
Eye Institute (i-32), Cleveland Clinic Foundation, Neurofibromatosis Type 1 (NF1)
Cleveland, OH, USA
A. D. Singh (*) Introduction
Cole Eye Institute, Cleveland Clinic,
Cleveland, OH, USA Several distinct forms of neurofibromatosis have
e-mail: [email protected] now been recognized [2]. The most common is

116 E. Binkley et al.
Table 9.1 Summary of organ system involvement in various phakomatoses

Clinical features
Disorder Neurological Ocular Cutaneous Visceral
Neurofibromatosis 1 Present Present Present Absent
Neurofibromatosis 2 Present Present Absent Absent
Von Hippel-Lindau disease Present Present Absent Present
Tuberous sclerosis complex (I) Present Present Present Present
Tuberous sclerosis complex (II) Present Present Present Present
Sturge-Weber syndrome Present Present Present Absent
Wyburn-Mason syndrome Present Present Absent Absent
Retinal cavernous hemangioma Present Present Absent Absent
Sebaceous nevus syndrome Present Present Present Absent
Ataxia telangiectasia Present Present Present Present
Neurocutaneous melanosis Present Variable Present Absent
Phakomatosis pigmentovascularis Variable Variable Present Absent
Table 9.2 Summary of inheritance pattern of various phakomatoses

Genetic
Disorder Inheritance locus Gene Protein Function
Neurofibromatosis 1 Autosomal 17q11 NF1 Neurofibromin Inhibits ras activity
dominant
Neurofibromatosis 2 Autosomal 22q12 NF2 Merlin/ Links cytoskeletal proteins
dominant schwannomin and cell membrane
Von Hippel-Lindau Autosomal 3p25 VHL pVHL Inhibits mRNA elongation
disease dominant
Tuberous sclerosis Autosomal 9q34 TSC1 Hamartin Regulates vesicular
complex (I) dominant movement
Tuberous sclerosis Autosomal 16p13 TSC2 Tuberin Inhibits GTP-binding
complex (II) dominant proteins
Sturge-Weber Sporadic 9q21 GNAQ Gaq Mediates signals between
syndrome (somatic) G-protein- coupled receptors
and downstream proteins
Wyburn-Mason Sporadic – – – –
syndrome
Retinal cavernous Autosomal 7q21.2, CCM1, KRIT1, Believed to be involved in
hemangioma dominant 7p13, CCM2, malcavernin, endothelial cell function
3q26.1 CCM3 PDCD10
Sebaceous nevus Sporadic – – – –
syndrome
Ataxia telangiectasia Autosomal 11q22 ATM ATM protein Protein kinase
recessive
Neurocutaneous Sporadic – – – –
melanosis
Phakomatosis Sporadic 19p13.3, GNA11, Ga11, Gaq Mediates signals between
pigmentovascularis 9q21 GNAQ G-protein- coupled receptors
(somatic) and downstream proteins
neurofibromatosis type 1 (von Recklinghausen Genetic Aspects

disease), followed by neurofibromatosis type 2
(also called central neurofibromatosis) [3]. Other NF1 is an autosomal-dominant disorder caused
less common types include multiple meningio- by mutations of the NF1 gene on chromosome
matosis, spinal schwannomatosis, and segmental 17q11.2 [4]. The penetrance of NF1 mutations is
neurofibromatosis [2, 4]. usually complete (100%) [5]. About 50% of all
9 Neuro-oculocutaneous Syndromes (Phakomatoses) 117
index cases are due to new mutations, and the Table 9.3 Criteria for the clinical diagnosis of neurofi-
bromatosis type 1 formulated by the National Institute of
large majority (90%) of new mutations are pater-
Health Consensus Development Conference
nal in origin [6]. A wide variety of NF1 mutations
Presence of any two or more of the following is
have been described without any genotype- diagnostic
phenotype correlation [7]. The large size of the Café-au-lait spots >5 mm in diameter in prepubertal
gene makes screening for mutations difficult. A (six or more) individuals
combination of techniques such as heteroduplex >15 mm diameter in postpubertal
analysis, fluorescent in situ hybridization (FISH), individuals
Neurofibroma Any type: two or more
and protein truncation assays results in a high
Plexiform: one or more
mutation detection rate (95%) [8]. Axillary and
inguinal freckles
Optic nerve One or more
Pathogenesis glioma
Lisch nodules One or more
A distinctive Sphenoid wing dysplasia
The NF1 gene codes for neurofibromin [4], a osseous lesion Congenital bowing or thinning of
cytoplasmic GTPase-activating protein that nega- the long bone cortex, with or
tively regulates oncoprotein ras [9]. Loss of NF1 without pseudoarthrosis
function in neurofibromas is limited to Schwann First-degree
cells, indicating that the Schwann cell is the cell relative with NF1
of origin of neurofibromas in NF1 [10, 11]. Based on data from Ref. [13]
Table 9.4 Ophthalmic manifestations of neurofibroma-

Clinical Features tosis type 1
Location Lesion Frequency (%)
NF1 is one of the most common genetic dis- Eyelid Nodular neurofibroma 18
orders with protean manifestations involving Plexiform neurofibroma 5
neural tissues [2]. The disease has a preva- Café-au-lait spots 3
lence of about 1/3000 with equal distribution Conjunctiva Neurofibroma 5
in a variety of ethnic groups [12]. The National Cornea Prominent corneal nerves 6–22
Posterior embryotoxon 3–5
Institutes of Health Consensus Development
Angle Congenital glaucoma 50
Conference has suggested clinical criteria diag- Uvea Lisch nodules 70–92
nostic for NF1 (Table 9.3) [13]. Significant ocu- Choroidal hamartoma 51
lar findings in NF1 are summarized in Table 9.4 Choroidal nevus 3–5
[14, 15]. Optic nerve Pilocytic astrocytoma 2–12
Optic disc drusen 1
Café-au-Lait Macules Modified from Lewis and Riccardi [14]. With permission
Large areas of flat cutaneous hyperpigmentation from Elsevier
are the most frequent and earliest findings and
occur in more than 99% of individuals with NF1 of life. They appear as discrete soft tumors on the
(Fig. 9.1a). These spots are present at birth and face, hands, and trunk (Fig. 9.1b). Based on their
increase in number and size during childhood. appearance and extent of tissue involvement,
Other forms of hyperpigmentation occur, such as neurofibromas can be classified as cutaneous,
axillary and intertriginous freckling. subcutaneous, nodular plexiform, and diffuse
plexiform.
Neurofibroma
Neurofibroma is the hallmark tumor and clinical Lisch Nodules
finding of NF1. Neurofibromas tend to be multi- The presence of melanocytic hamartomas of the
ple and develop toward the end of the first decade iris, known eponymously as Lisch nodules, is
a b
Fig. 9.1 Common manifestations of NF1. Café-au-lait macules (a), multiple neurofibromas of the face (b), multiple
Lisch nodules (c), optic nerve glioma (d), and contrast-enhanced magnetic resonance image
highly characteristic of NF1 [16, 17]. Lisch nod-

ules are typically multiple, are tan-colored, and Glaucoma
are best detected with the slit lamp on the ante- Glaucoma is common in patients with NF1.
rior iris surface, mostly inferiorly (Fig. 9.1c). There is an association between glaucoma and
The prevalence of Lisch nodules gradually plexiform neurofibroma of the upper eyelid.
increases from birth to about 50% at 5 years, Another feature that can be noted is the pres-
75% at 15 years, and more than 90% in adult- ence of ectropion uvea (at the pupil margin).
hood [14, 18]. This is present in NF1 and may be secondary to
endothelialization of the anterior chamber
ptic Nerve Glioma
O angle. It is associated commonly with severe
Optic nerve gliomas are pilocytic hamartomas of pediatric glaucoma in these patients. The endo-
the anterior visual pathways. Other, more poste- thelial cell proliferation may be related to over-
rior, gliomas represent more aggressive variants expression of the Ras (Rat sarcoma)-MAPK
[19]. Gliomas occur in about 15% of patients genes in these eyes [22].
with NF1 (Fig. 9.1d) [20]. Bilateral optic nerve On occasion, neurofibromas may be pres-
involvement is believed to be pathognomonic of ent on the lid, brow, or face of an infant or
NF1, whereas unilateral tumors tend to be unre- child, a circumstance commonly referred to
lated to this syndrome [21]. as “orbitofacial neurofibromatosis” (OFNF).
In one study, glaucoma was found to be more Treatment

common in the ipsilateral side in the eyes
with orbitofacial involvement and was associ- Once the diagnosis of NF1 is made, patients need
ated with globe enlargement [23]. Visual loss referral to a provider with expertise in managing
in patients with orbitofacial neurofibromatosis NF1 for evaluation and counseling regarding the
(OFNF) is common, typically profound, and prognosis, genetics, and psychological aspects of
usually multifactorial. The causes of visual the disease [31, 32]. First-degree relatives should
loss include congenital glaucoma with buph- also be assessed for signs and symptoms consis-
thalmos and retinal detachment, disconjugate tent with NF1 [31]. Care of patients with NF1 is
gaze due in part to distorted skull development complex and may require coordination with
causing strabismic amblyopia, and optic nerve experts from multiple subspecialties including
glioma. These are difficult to treat adequately dermatology, genetics, neurology, neurosurgery,
and tend to cause progressive, profound visual oncology, ophthalmology, orthopedics, radiology
loss. Therefore, careful observation should be pediatrics, and plastic surgery [25, 31, 32].
made during the period of visual immaturity Children with NF1 should be examined with an
for causes of amblyopia that might be treat- annual physical exam with special attention given
able, such as refractive changes, occlusion of to the neurologic exam, skin exam, and monitor-
the visual axis, and congenital glaucoma. As ing for the development of hypertension that
affected individuals get older, physicians must could be due to renal artery stenosis or pheochro-
be vigilant for progressive optic nerve damage mocytoma [27, 31]. They should additionally
caused by glaucoma or optic nerve glioma and have an ophthalmic exam every 6–12 months
must be alert to the possibility of improving from 0–8 years and every 1–2 years until they
vision by refraction [24]. turn 18 [27, 33]. Exams should include an assess-
ment of visual acuity, pupils, optic disc appear-
Other Malignancies ance, and ocular motility [27, 33]. Visual fields
Patients with NF1 also have increased and life- and color vision should be assessed once the
long risks of developing a variety of malignant patient is able to cooperate with these tests [27,
tumors, which include breast cancer, duodenal 33]. If an optic glioma is diagnosed, MRI should
carcinoid tumors, glioblastoma and other brain be performed four times a year for 1 year with an
tumors, gastrointestinal stromal tumors, leuke- increase in the imaging interval over the subse-
mia, malignant peripheral nerve sheath tumors, quent 2–3 years [25]. The management of optic
pheochromocytoma, and rhabdomyosarcoma nerve glioma remains controversial, and treat-
[25]. Clinicians need to be aware of these asso- ment is generally initiated when there is concern
ciations so that patients can be appropriately for a risk of permanent vision loss [33]. These
monitored for symptoms associated with the lesions are often treated with chemotherapy;
development of these tumors [25–29]. radiation is avoided because of the risk of induc-
ing secondary malignancy [25]. Therapeutic indi-
cations and outcomes with various forms of
Diagnostic Evaluation management, which include observation, chemo-
therapy, excision, and radiotherapy, are discussed
The NIH consensus criteria are useful for estab- in detail under optic nerve tumors. Children diag-
lishing the diagnosis of NF1 in adults as well as in nosed with orbital plexiform neurofibromas
young children. MRI is particularly helpful in should also be assessed at least every 6 months
detecting optic nerve gliomas. Characteristic prior to age 8 to monitor for amblyopia [34].
“bright lesions” on MRI are present in about 15% While the timing of surgical intervention is con-
of patients with NF1 (Fig. 9.1e). The high-signal troversial, treatment is usually indicated in chil-
T2 lesions are present in the cerebral hemispheres, dren under 10 years of age with concern for
brainstem, and cerebellum [30]. amblyopia [34].
Prognosis Genetic Aspects
Some patients with NF1 have mental retardation, The inheritance pattern is autosomal dominant
learning difficulties, and other behavioral problems with complete penetrance. There is some evi-
[35]. It is important to note that some manifesta- dence to suggest that maternally inherited cases
tions of NF1 tend to develop or increase over time have an earlier onset than paternally inherited
and are not always present at initial diagnosis [36]. cases (18 years vs. 25 years) [38]. About 50%
For example, Lisch nodules and cutaneous neurofi- of the cases represent new mutations [39]. There
bromas appear more commonly in teenage and is some evidence for genotype-phenotype cor-
young adult patients, while pheochromocytoma relation because patients with truncating NF2
and paraspinal plexiform neuroma are more com- mutations are usually associated with severe phe-
mon in adults [36]. Although the majority of tumors notypes, while those with single codon altera-
in NF1 are benign, their location in the CNS can tions have mild NF2 [38, 40]. The NF2 gene
lead to significant morbidity. The risk of develop- has been mapped to chromosome 22q12 [41]. It
ing malignant tumors, particularly of the peripheral encodes a 587 amino acid protein known as mer-
nerve sheath, is about 5%, and there is also an lin or schwannomin.
increased risk of early death from malignancy [37].
Pathogenesis
Neurofibromatosis Type 2 (NF2)
Merlin acts as a tumor suppressor gene [42].
Introduction Disruption of merlin-dependent links of mem-
brane proteins to the cytoskeleton leads to tumor
NF2 is also called “central NF” because the formation [43].
majority of its manifestations are related to cen-
tral nervous system involvement. Unlike NF1,
cutaneous findings are not a predominant feature Clinical Features
of NF2. In contrast to neurofibromas that are
hallmarks of NF1, schwannomas are the charac- The prevalence of NF2 is 1 in 33,000–40,000
teristic tumors of NF2 (Table 9.5). [39]. One percent of patients with meningioma
and 3% of patients with schwannomas have NF2
Table 9.5 Criteria for the diagnosis of neurofibromatosis [43]. Bilateral vestibular schwannomas (VS) are
type 2 diagnostic of NF2 (Fig. 9.2a). Ocular abnormali-
Presence of any ties are present in more than two-thirds of NF2
one of the cases, and common findings include cataracts
following Features
Bilateral
and retinal hamartomas [44]. The ocular features
vestibular manifest themselves in childhood and a dolescence
schwannoma and are therefore extremely useful in early diag-
First- Plus Unilateral vestibular schwannoma nosis of NF2 [45].
degree <30 years
relative
with NF2 Vestibular Schwannoma
First- Plus Any two of the following: Ninety-five percent of patients with NF2 have
degree meningioma, glioma, schwannoma, bilateral VS [46]. The mean age of symptom
relative juvenile posterior subcapsular onset is around 25 years [47]. This is important
with NF2 lenticular opacities/juvenile cortical
cataract for the ophthalmologist to note since ophthal-
The criteria were formulated based on data from the National
mic findings may precede the development of
Institute of Health Consensus Development Conference symptoms from VS and identification of char-
(Neurofibromatosis: Conference Statement [13]) acteristic ophthalmic findings may help to lead
a b
Fig. 9.2 Bilateral vestibular schwannoma on gadolinium-enhanced magnetic resonance imaging is diagnostic of NF2
(a). Fundus photograph of a combined hamartoma of the retina and the retinal pigment epithelium (b)
to an earlier diagnosis of NF2 [47, 48]. ings of the outer layers, gliosis, and associated
Symptoms, though, are most commonly due to disorganized proliferation of blood vessels and
VS rather than ocular involvement. Deafness retinal pigment epithelium [54]. Bilateral com-
with or without tinnitus is most common. bined hamartomas of the retina and retinal pig-
Seizures, vertigo, and numbness are less com- ment epithelium (RPE) in a young child should
mon [49]. There is increased morbidity in NF2 alert the clinician to the possibility of neurofibro-
patients with VS due to an increased tumor matosis type 2 [55] (Fig. 9.2b).
growth rate [46]. The specific biomicroscopic and optical
coherence tomography (OCT) features of the
Ophthalmic Findings epiretinal membranes (ERM) associated with
Characteristic ocular manifestations of NF2 NF2 include edges that project anteriorly into
include posterior subcapsular cataracts, com- the vitreous despite an incomplete posterior
bined hamartoma of the retina and retinal vitreous detachment, lack of cystoid macu-
pigment epithelium (RPE), and epiretinal mem- lar edema, mild undulation of retinal laminae,
branes. Patients may also develop optic disc atro- and an irregular and partially absent internal
phy caused by optic nerve sheath or intracranial limiting membrane. With ERMs that cover the
meningioma, and recent work has also suggested foveal center, the inner retinal layers usually
that strabismus is more common in patients are not displaced centrifugally from the umbo
with neurofibromatosis 2 (Box 9.2) [44, 50–53]. [48]. Recognition of ERM with a characteristic
Children with vestibular schwannomas are usu- OCT appearance may permit early diagnosis in
ally asymptomatic, and ocular findings are there- neurologically asymptomatic children with a
fore of diagnostic significance. In a clinical study severe phenotype of NF2. Unlike idiopathic or
of 49 patients with NF2 and their offspring, poste- secondary ERMs that commonly result from
rior subcapsular/capsular, cortical, or mixed lens other ocular conditions such as posterior vitre-
opacities were the most common ocular abnor- ous separation, proliferative vitreoretinopathy,
malities and were present in 67% of patients [45]. inflammation, vascular disorders, or trauma,
Combined hamartoma of the sensory retina and NF2-specific ERMs are congenital lesions that
RPE is described as thickened retina with infold- may enlarge over time [48].
ox 9.2 Characteristic Ocular

B established a relationship between cerebellar
Abnormalities in Neurofibromatosis 2 and retinal hemangioblastomas [60]. It was not
until 1964 that Melmon and Rosen established
the clinical spectrum of “von Hippel-Lindau”
• Cataracts: posterior subcapsular, capsu- disease (VHL) when they reported cases of “von
lar, cortical, and mixed Hippel’s disease” and “Lindau’s disease” with
• Retinal hamartoma overlapping manifestations [61]. Since then sev-
• Epiretinal membrane eral investigators have studied the natural his-
tory of the disease and developed screening
protocols [62–64].
Genetic Aspects
Genetic testing is recommended for children of
individuals affected with NF2 given that the clin- VHL disease follows an autosomal-dominant
ical features may not meet the criteria for diagno- mode of inheritance with a 90% penetrance by
sis until later in life [46]. Patients suspected to the age of 60 [62, 65]. Following the identifica-
have NF2 are usually screened by neurological, tion of the VHL gene on chromosome 3p25-26 in
ophthalmic, and neuro-otologic testing. Magnetic 1993, genetic testing with very high detection
resonance imaging (contrast-enhanced, multi- rates (99%) has become commercially available
planar T1-weighted sequences) is a cost-effective [66, 67]. Because of significant social and ethi-
first-line investigation in the detection of VS [56]. cal issues associated with genetic testing,
patients considering the genetic testing for the
VHL disease should undergo expert genetic
Treatment counseling [68].
The management of vestibular schwannomas

involves complex decision-making and choos- Pathogenesis
ing among various options that include observa-
tion, stereotactic radiotherapy, and surgical The VHL gene encodes a 213 amino acid protein
resection [57]. that binds with elongin B, elongin C, and Cul 2 to
form a complex that targets hypoxia-inducible
factors (HIFs), which are the transcription factors
Prognosis that promote angiogenesis, for degradation by
proteasomes [69–71]. In the absence of VHL pro-
Patients with NF2 have a reduced life expectancy. tein (pVHL), there is excessive production of
Early age of onset, presence of truncating muta- vascular endothelial growth factor [69, 70]. Using
tions, and increased number of meningiomas are tissue microdissection technique and PCR, it is
associated with a worse prognosis [38, 58]. now believed that the true neoplastic component
(i.e., the cells with allelic deletion at the VHL
gene locus) is the foamy stromal cell within the
Von Hippel-Lindau Disease capillary hemangioma [70].
Introduction
Clinical Features
Eugen von Hippel, a German ophthalmologist,
coined the term angiomatosis retinae in 1904 The incidence of VHL disease is 1 in 40,000 to
[59]. Arvid Lindau, a Swedish pathologist, 1 in 54,000 live births. It is estimated that there
Table 9.6 Diagnostic criteria for von Hippel-Lindau etinal Capillary Hemangioma
R
disease
Retinal capillary hemangiomas (RCH) are
Family Required feature the most common tumor in VHL patients and
historya Any one of the following often occur earlier than other tumors [62, 78].
Positive One or more retinal capillary
hemangioma
Therefore, the ophthalmologist is frequently
One or more CNS hemangioma involved in the care of patients with VHL dis-
One or more visceral lesionsb ease. The clinical features of VHL disease are
Negative Two or more retinal capillary discussed elsewhere (Chap. 3). The prevalence
hemangiomas of underlying VHL disease in patients with soli-
Two or more CNS hemangiomas tary or multiple RCH is reported to be 20–58%
One retinal hemangioma with a visceral
lesion
[79]. The presence of multiple RCH (two or
One CNS hemangioma with a visceral more), other manifestations of VHL disease, or a
lesion positive family history indicates the presence of
a
Family history of the following: retinal hemangioma, underlying VHL disease.
CNS hemangioma, or visceral lesion RCHs are unilateral in 42% and bilateral
b
Visceral lesions include the following: renal cysts, renal in 58% of patients. No correlation has been
carcinoma, pheochromocytoma, pancreatic cysts, islet
cell tumors, epididymal cystadenoma, endolymphatic sac detected between the age, sex, and laterality of
tumor, adnexal papillary cystadenoma of probable meso- involvement. Eighty-six percent of involved eyes
nephric origin have tumors that can be individually visualized.
Tumors are commonly found in the peripheral
are approximately 7000 patients with VHL dis- retina (85%) only and less commonly in the jux-
ease in the United States [72]. VHL disease is a tapapillary area (15%). Severe visual impairment
multisystem disorder with the predilection for (visual acuity = 20/160 or worse) in affected
tumors of the retina and the central nervous eyes is more likely to be associated with increas-
system (CNS). Significant clinical manifesta- ing age, the presence of juxtapapillary lesions,
tions of VHL disease are included in the diag- and a greater number and extent of peripheral
nostic criteria (Table 9.6). Retinal capillary lesions [80].
hemangiomas (RCH) occur in less than 75% of
cases, CNS hemangiomas in more than 50% of entral Nervous System Hemangioma
C
cases, renal carcinomas in less than 50% of Commonly involved sites include the cerebellum
cases, and pheochromocytomas in less than (75%) and spinal cord (15%) [62]. The CNS
25% of cases [62]. Polycythemia can be seen in hemangiomas associated with VHL disease tend
up to 17% of patients [73]. The cumulative to be multiple and occur at a younger age as com-
probability of manifesting RCH, CNS heman- pared to sporadic cases. Headache is the most
gioma, and renal cell carcinoma increases with frequent initial symptom of cerebellar hemangio-
age (Fig. 9.3a) [62]. mas, and pain is the most common symptom of
There seems to be a correlation between the spinal cord hemangiomas (Fig. 9.3b) [81].
type of VHL gene mutation and the clinical fea- Pregnancy in patients with VHL disease can
tures (genotype-phenotype correlation), which induce the progression of cerebellar hemangio-
has led to a new classification of VHL disease blastoma, and there is a high VHL disease-related
(Table 9.7) [74, 75]. However, a variety of pheno- pregnancy complication rate [82].
types can be caused by mutations in the same
codon, suggesting that factors such as modifier enal Cell Carcinoma
R
genes, environmental factors, and the specific Renal cell carcinoma is one of the leading causes
amino acid substituted may also play a role [76]. of mortality in VHL disease [62, 83, 84]. The risk
There does not appear to be a specific type of of developing renal cancer in patients with VHL
germline mutation that correlates with the pres- increases with age. Approximately 70% of patients
ence of RCH [77]. will develop renal cell cancer if they live to the age
Fig. 9.3 Cumulative a
probability of
developing retinal Cumulative probability
capillary hemangioma, 1
cerebellar hemangioma, 0.9
and renal cell carcinoma 0.8
in von Hippel-Lindau 0.7
disease (a). Magnetic 0.6
resonance image (T2
0.5
weighted) of a
cerebellar hemangioma 0.4
appearing as a cystic 0.3
lesion (b). A, based on 0.2
data from Ref. [62] 0.1
0
0 10 20 30 40 50 60 70
Age (years)
RCH CHB RCC
Table 9.7 National Cancer Institute classification of von Hippel-Lindau disease

Clinical features
Type CNS hemangioma RCH RCC Pheochromocytoma Mutation
I Present Present Present Absent Deletions
Insertion
Nonsense
IIA Present Present Absent Present Missense
IIB Present Present Present Present
IIC Absent Absent Absent Present
CNS central nervous system, RCH retinal capillary hemangioma, RCC renal cell carcinoma
of 60 years [84]. Compared to patients with spo- Table 9.8 National Institutes of Health (USA) screening
protocols for patients with or at risk for von Hippel-
radic tumors, patients with VHL are more likely to
Lindau disease
have bilateral and multifocal disease [84].
Age
Investigation (years) Frequency
Pheochromocytoma Urinary catecholamine From Every year
Pheochromocytomas are rare benign tumors of age 2
the adrenal medulla. In patients with VHL dis- Ophthalmoscopy From Every year
ease, they tend to be multiple and bilateral [85]. age 1
Enhanced MRI brain and 11–60 Every 2 years
Absence (type I) or presence (type II) of pheo-
spine 61 and Every 3–5 years
chromocytoma forms the basis of National above
Cancer Institute classification of the VHL disease Abdominal USG 11–20 Every year
(Table 9.7). Pheochromocytoma produces ele- Abdominal CT From Every 1–2 years
vated serum levels of catecholamines (norepi- age 21
nephrine and epinephrine), which cause CT computed tomography, MRI magnetic resonance
symptoms such as palpitations, headaches, and imaging, USG ultrasonography
sweating, sometimes simulating anxiety attacks.
Other Cancers Treatment

Pancreatic tumors and cystadenoma of the epi-
didymis occur less commonly than other tumors. The decision to treat RCH and various meth-
Endolymphatic sac tumor, present in 11% of ods of management are discussed elsewhere
patients, is a recently recognized feature of VHL (Chap. 3). Details of treatment of other organ
disease [86]. involvement are beyond the scope of this chap-
ter. Treatment options for RCH may include
laser photocoagulation, photodynamic ther-
Diagnostic Evaluation apy (PDT), cryotherapy, and external beam
radiation [78]. While there are no large-scale
The retinal findings of RCH are usually typical, studies investigating the use of intravitreal
and the diagnosis can be usually made based on anti-VEGF injections in treating RCH, several
ophthalmoscopic examination and fluorescein case reports and case series have suggested
angiography. Gadolinium-enhanced magnetic effectiveness either alone or in combination
resonance imaging is the diagnostic method of with PDT [88–90].
choice for CNS hemangioma [81]. Asymptomatic
renal, adrenal, and other organ involvement can
be detected by enhanced computed tomography Prognosis
[64] and 24-h urinary biochemical excretion
tests. Patients with or at risk for VHL disease The complications of RCH can be severe and
should be screened as per National Institutes of visually significant even in adequately treated
Health screening protocol (Table 9.8). cases. More than 25% of patients with RCH
Recently, quantitative studies have been devel- show permanent visual loss (vision of <20/40 in
oped that enable a full characterization of the one or both eyes) [77]. VHL disease is associ-
impact of von Hippel-Lindau disease on eye health ated with significant morbidity from CNS hem-
and visual function. Establishing correlations angioma and renal cell carcinoma. In addition,
between the genotype of the von Hippel-Lindau there is significant mortality from renal cell car-
mutation and the phenotype of eye disease may cinoma [62]. Recent work has shown that the life
inform us as to how ocular von Hippel-Lindau dis- expectancy of people with VHL is improving,
ease arises and could help guide molecular inter- likely due to improved surveillance and treat-
ventions in ocular von Hippel-Lindau disease [87]. ment protocols [83].
Tuberous Sclerosis Complex ungual fibromas, hypomelanotic macules, and

shagreen patches) are mainly of diagnostic sig-
Introduction nificance. Ocular findings can include astrocytic
hamartomas involving the retina and optic disc,
The name tuberous sclerosis was suggested hypopigmented areas and hamartomas of the
by the French physician Désiré-Magloire uveal tract, colobomas of the iris and choroid,
Bourneville (1840–1909), who dedicated his and eyelid angiofibromas [97]. Visceral
life to the study of mentally abnormal and epi- hamartomas most commonly involve the lungs,
leptic children. In 1880, Bourneville described kidney, and heart [92]. The classic triad of
a patient with seizures, hemiplegia, mental epilepsy, mental retardation, and adenoma
subnormality, and renal tumors. He based the sebaceum is present in only one-third of cases
terminology tuberous sclerosis on the neuro- (Table 9.9) [75].
pathologic observations of multiple potato-like In general, the clinical manifestations of TSC1
(tubers) lesions in the brain [91]. and TSC2 are similar except that TSC1 repre-
sents a milder phenotype with a reduced risk of
mental retardation as compared to TSC2 [99].
Genetic Aspects Other findings of TSC1, such as seizures, renal
involvement, facial angiofibroma, and retinal
Tuberous sclerosis complex (TSC) includes two
genetic diseases (TSC1 and TSC2), both with
autosomal-dominant inheritance and high pene-
trance (95%) [92]. Two-thirds of cases are spo- Table 9.9 Revised diagnostic criteria for tuberous scle-
radic and result from fresh genetic mutations. rosis complex
The genes responsible for TSC, TSC1 (chromo- Definite diagnosis Two major features
some 9q34) [93], and TSC2 [94] have now been One major feature plus
identified. two minor features
Probable diagnosis One major feature plus
one minor feature
Possible diagnosis One major feature
Pathogenesis Two minor features
Major features Minor features
Tuberous sclerosis is associated with mutations 1. Facial angiofibroma or 1. Multiple dental
in the TSC1 and TSC2 genes, which encode forehead plaque enamel pits
hamartin and tuberin, respectively. Hamartin and 2. Ungual/periungual 2. Hamartomatous
fibroma rectal polyps
tuberin interact with each other as well as over 50
3. Hypomelanotic macules 3. Bone cysts
other proteins and influence a common cellular (three or more)
pathway [95, 96]. These findings provide the 4. Shagreen patch 4. Cerebral white matter
basis for identical clinicopathologic manifesta- migration lines
tions of TSC1 and TSC2 that result when either 5. Multiple retinal 5. Gingival fibromas
of these proteins is inactivated or abnormal in hamartomas
6. Cortical tuber 6. Nonrenal hamartoma
structure.
7. Subependymal nodule 7. Retinal achromic
patch
8. Subependymal giant-cell 8. “Confetti” skin
Clinical Features astrocytoma lesions
9. Cardiac rhabdomyoma 9. Multiple renal cysts
(one or more)
Tuberous sclerosis is characterized by hamarto-
10. Lymphangiomyomatosis
mas of various organs. The hamartomas in the 11. Renal angiomyolipoma
brain (astrocytoma and ependymoma) lead to The criteria were formulated based on data from the
childhood seizures and mental retardation. The tuberous sclerosis complex consensus conference 1998
skin manifestations (facial angiofibromas, sub- (Roach et al. [98])
hamartomas, are also less frequent or less severe A population-based survey of patients with
compared to TSC2 [100]. TS confirmed the presence of retinal hamarto-
mas in 44% cases (of which 70% eyes had flat,
etinal Astrocytic Hamartoma
R translucent lesions; 55% eyes had multinodu-
Approximately one-third to one-half of patients lar “mulberry” lesions; and the transitional
with TSC have retinal or optic nerve hamarto- type lesion was seen in 9% eyes). Punched-out
mas, and the hamartomas occur bilaterally in half areas of chorioretinal depigmentation were
of these patients [101]. Clinical features of retinal seen in 39% eyes (Fig. 9.4a). Approximately
astrocytic hamartoma are discussed in detail 40% of patients have angiofibromas of the
elsewhere (Chap. 4). eyelids [102].
a b
Fig. 9.4 Common manifestations of TSC. Retinal achro- magnetic resonance image and cardiac rhabdomyoma (d).
mic patch (a). The hypomelanotic macules “ash-leaf” sign (Reprinted from Seki et al. [107]. With permission from
(b), multiple subcortical tubers (c), T2-weighted axial American Medical Association)
rain and Neurological Manifestations

B Treatment
Epilepsy, mental retardation, and behavior prob-
lems are the most significant clinical manifesta- The treatment of TSC depends upon the loca-
tions that cause most of the morbidity associated tion and the extent of organ involvement. Retinal
with TSC. As evident from the revised diagnos- astrocytic hamartomas usually need only periodic
tic criteria, neurological manifestations are not evaluation by ophthalmoscopy and fundus pho-
necessary for the diagnosis of TSC. Epilepsy tography. Symptomatic changes are very rare in
may present as infantile spasms. About 50% of retinal hamartomas secondary to tuberous sclero-
TSC patients are mildly to profoundly mentally sis. They can cause vision loss through local reti-
retarded. The severity of neurological disease nal degeneration or the production of subretinal
directly correlates with the extent and number and intraretinal fluid [110]. Spontaneous resolu-
of cortical tubers detected on MRI scans tion of subretinal fluid may occur within 4 weeks.
(Fig. 9.4c) [103]. If macular edema with increasing lipid exudates
persists for longer than 6 weeks, treatment should
Skin Manifestations be considered. Although some reports demon-
Cutaneous manifestations of TSC are mainly strated possible visual stabilization after argon
of diagnostic significance (Fig. 9.4b). The laser photocoagulation, vision-threatening com-
hypomelanotic macules are the most frequent plications can occur. Current treatment strategies
and the earliest finding of TSC and occur in may include PDT based on recent favorable ana-
up to 97% of children (Fig. 9.4b) [104]. They tomical and functional results [111]. Intravitreal
are best visualized with Wood’s lamp (UV bevacizumab and intravitreal steroids have also
light). Fibrous plaques appear as reddish orange been used to manage symptomatic lesions [110].
patches on the forehead. Facial angiofibromas Given that mutations in the TSC1 and TSC2
are not present at birth and usually appear by genes result in dysregulation of the mammalian
age 5 years. Subungual fibromas appear later in target of rapamycin (mTOR) pathway, a num-
life [105]. ber of recent studies have investigated the use of
mTOR inhibitors such as everolimus and siroli-
Visceral Manifestations mus for the treatment of tumors associated with
Visceral manifestations of TSC include pulmo- tuberous sclerosis. This work has shown promise
nary lymphangiomyomatosis [105], renal angio- in using systemic everolimus to treat aggressive
myolipoma [106], and cardiac rhabdomyoma retinal astrocytic hamartoma, cardiac rhabdo-
(Fig. 9.4d) [107]. myomas, and renal angiomyolipoma [112–118].
Topical sirolimus has been used to success-
fully treat cutaneous lesions in a small series of
Diagnostic Evaluation patients [117].
The diagnosis of TSC is clinically based on

diagnostic criteria [98]. Imaging studies such as Prognosis
magnetic resonance imaging of the brain and
computerized tomography of the abdomen are Retinal astrocytic hamartomas are generally sta-
important to detect CNS and visceral involve- ble with slow growth over several years or new
ment [108]. Individuals with retinal findings are calcification in some cases [101]. TSC leads to
more likely to have concomitant subependymal significant morbidity mainly due to neurological
giant-cell astrocytomas, renal angiomyolipo- and visceral involvement. The majority (85%) of
mas, cognitive impairment, and epilepsy. TSC2 patients with TSC-related mental retardation
mutations are more frequent in patients with require supervision for daily living. In general,
retinal findings than in those without retinal patients with TSC have reduced survival as com-
findings [109]. pared to the general population. The common
causes of mortality are renal disease, brain activation of the ERK pathway but has only a
tumors, and status epilepticus. Patients with TSC limited effect on the JNK pathway. The effects
need lifelong follow-up for early detection of on these pathways may result in the findings seen
potentially life-threatening complications [108]. in Sturge-Weber syndrome by increasing basal
signaling downstream of Gaq or by dysregulating
G-protein-coupled receptor signaling for proteins
Sturge-Weber Syndrome such as endothelin during development, which
could result in the vascular abnormalities seen
Introduction in Sturge-Weber syndrome [121]. The precise
mechanism by which these mutation result in this
In 1879, Sturge described a syndrome character- syndrome remains under investigation [121].
ized by a facial hemangioma, ipsilateral buph-
thalmos, and contralateral seizures [119]. Weber
in 1922 described radiological evidence of cor- Clinical Features
tical calcification secondary to leptomeningeal
hemangioma causing hemiplegia [120]. Since Infantile glaucoma and diffuse choroidal heman-
both descriptions applied to the same entity, the gioma may be associated with some visual loss.
triad of leptomeningeal hemangioma, choroidal Sturge-Weber syndrome with its neural involve-
hemangioma, and cutaneous hemangioma has ment leads to intractable seizures, developmental
been called Sturge-Weber syndrome (SWS). In delay, and behavioral problems. The cutaneous
the absence of CNS involvement, patients should manifestations of nevus flammeus, although most
only be given a diagnosis of port-wine stain or evident, are mainly of diagnostic significance
facial angioma to avoid the stigmata associated (Table 9.10). Differential diagnoses for Sturge-
with a diagnosis of Sturge-Weber syndrome. The Weber syndrome include Klippel-Trenaunay and
predominant manifestation is a diffuse heman- Beckwith-Wiedemann syndromes.
gioma of the leptomeninges, the choroid, and
the facial skin. The other term for this disorder, Glaucoma
encephalofacial hemangiomatosis, emphasizes Glaucoma is the most frequent manifestation of
only the non-ocular manifestations. SWS and occurs in about 70% of all cases [122].
Various pathogenetic mechanisms, such as angle
maldevelopment or raised episcleral venous
Genetic Aspects pressure, can lead to glaucoma [123]. The glaucoma
is usually diagnosed in the first 2 years of life;
Unlike other phakomatoses, Sturge-Weber however, there is a lifetime risk of developing
syndrome is not inherited. Recent work has
shown that Sturge-Weber syndrome is likely Table 9.10 Clinical features of Sturge-Weber syndrome
caused by somatic activating mutations in the Organ system Clinical features
gene GNAQ [121]. Central nervous Leptomeningeal angiomatosisa
system Cortical atrophy
Seizures
Pathogenesis Developmental delay
Behavioral problems
Eye and adnexa Nevus flammeus
Shirley et al. have identified somatic activat-
Prominent episcleral vessels
ing mutations in GNAQ as the likely etiology Glaucoma
of Sturge-Weber syndrome [121]. They hypoth- Diffuse choroidal
esize that the GNAQ mutation in Sturge-Weber hemangiomaa
syndrome differs from the GNAQ mutations seen Cutaneous Nevus flammeusa
in uveal melanoma in that it results in moderate Any two of the three features essential for diagnosis
a
glaucoma. The incidence of glaucoma is higher if

a
the eyelids are involved with nevus flammeus [124].
iffuse Choroidal Hemangioma

D
About half of the patients with SWS have a dif-
fuse choroidal hemangioma [122]. The choroidal
hemangioma is usually unilateral and ipsilateral
to the nevus flammeus. The clinical features of
choroidal hemangioma are discussed in detail
under uveal vascular tumors.
Leptomeningeal Hemangiomatosis b
The leptomeningeal hemangiomatosis is ipsilat-
eral to the cutaneous involvement. This can lead
to seizure disorder due to the effects on underly-
ing cerebral cortex. Seizures are present in about
80% of all patients with SWS with onset within
the first year of life [125]. There is a correlation
between early onset of seizures and the likeli-
hood of developmental delay and behavior prob-
lems [126].
Nevus Flammeus
The cutaneous hemangioma is also called nevus Fig. 9.5 Typical facial distribution of cutaneous heman-
flammeus or port-wine stain (Fig. 9.5a). In gen- gioma (a) and leptomeningeal hemangioma (b) in Sturge-
eral, only about 10% of all nevus flammeus Weber syndrome
cases are associated with SWS [127]. SWS only
occurs in patients who have involvement in the
region of V1 or V2 distribution of the trigeminal Treatment
nerve [127]. Bilateral port-wine stains have a
higher likelihood of being associated with SWS Medical therapy of glaucoma is effective in
than unilateral lesions. Conversely, leptomenin- some cases [124], but many patients eventually
geal and ocular involvement in SWS is always require multiple trabeculectomies, combined
associated with port-wine stain involving the trabeculotomy with trabeculectomy (Mandal
eyelids, the upper eyelid more often than the [129]), or even drainage implants [130]. The
lower eyelid [127]. choroidal hemangioma can be treated with
low-dose standard radiotherapy or with proton
beam radiotherapy [131, 132]. The treatment
Diagnostic Evaluation of choroidal hemangioma is discussed under
uveal vascular tumors. Seizures are generally
Contrast-enhanced MRI is most suited for detect- controlled with medications, but intractable
ing cerebral atrophy and leptomeningeal angio- cases require surgical resection of the lepto-
matous malformations (Fig. 9.5b) [128]. If the meningeal angiomatosis with underlying
MRI is normal, CT scan should be used to detect cerebral cortex [133].
intracranial calcifications. PDT is an effective treatment option for visual
deterioration from exudative retinal detachment
in patients with diffuse choroidal hemangiomas
[104–106, 134–136].
Prognosis Table 9.11 Clinical features of Wyburn-Mason

syndrome
Only limited information is available about Organ system Clinical features

the long-term prognosis of patients with Central nervous system Racemose hemangioma
Retina Racemose hemangioma
SWS. Mental retardation and behavioral and
Orbit Racemose hemangioma
social problems are more common in older
children. Overall, about 40% of patients with
SWS are self- sufficient, and about 50% get mations have retinal arteriovenous malforma-
married [125]. tions (Table 9.11) [139].
etinal Arteriovenous Malformation

R
Wyburn-Mason Syndrome The ophthalmoscopic appearance of the retinal
arteriovenous malformation is striking with
Introduction dilated and tortuous retinal vessels extending
from the optic disc to the retinal periphery.
In 1943, Wyburn-Mason described several cases Similar arteriovenous malformations within the
of racemose hemangiomas of the retina and brain orbit, with or without retinal changes in the set-
and established an association between these vas- ting of WMS, have also been reported [140].
cular malformations [137]. Some authors refer The clinical features of retinal arteriovenous
to this entity as Bonnet-Dechaume-Blanc syn- malformations are described in detail elsewhere
drome [138]. Unlike other phakomatoses, there (Chap. 3).
is no cutaneous involvement in Wyburn-Mason
syndrome. Intracranial Arteriovenous
Malformation
The intracranial arteriovenous malformations in
Genetic Aspects the chiasmal region can lead to neuro-ophthalmic
presentations [141]. Patients present in the second
Wyburn-Mason syndrome is a nonhereditary or third decades of life with signs and symptoms
sporadic disorder. of acute cerebral or subarachnoid hemorrhage,
such as severe headache, nuchal rigidity, and loss
of consciousness.
Pathogenesis There is a distinct difference between patients
with congenital retinocephalofacial vascular
The pathogenesis of the vascular abnormalities in malformation syndrome and those with isolated
Wyburn-Mason syndrome is not understood. retinopathy without cerebral or facial malforma-
tions. Extensive retinal malformations of vessels
of most parts of the fundus occur more often in
Clinical Features patients with retinal and cerebral arteriovenous
malformations. In contrast, local retinal arte-
The clinical findings are usually congenital in riovenous malformations occur in all patients
origin, but the diagnosis is generally not made with isolated retinopathy without cerebral or
until later in childhood as there are no promi- facial malformations and rarely in patients with
nent external features. A review of published congenital retinocephalofacial vascular malfor-
cases indicates that the incidence of intracra- mation syndrome. Hence, patients with arterio-
nial arteriovenous malformations in patients venous communications of the retina should be
with retinal arteriovenous malformations examined early with brain and orbital neuroim-
is 30% [139]. Conversely, only about 8% of aging to rule out cerebral arteriovenous malfor-
cases with intracranial arteriovenous malformations [142].
Retinal Cavernous Hemangioma
Introduction
Retinal cavernous hemangioma is a rare benign

vascular tumor. Clinically, two forms are rec-
ognized: sporadic and syndromic [145]. Retinal
cavernous hemangiomas can be associated
with cerebral cavernous malformations as an
autosomal-dominant syndrome with high pen-
etrance and variable expressivity [146, 147]. It
Fig. 9.6 The intracranial arteriovenous malformation has been suggested that the cerebral cavernous
seen on arteriography malformation syndromes should be included
with the neuro-oculocutaneous (phakomatoses)
syndromes, but the association of cerebral and
Diagnostic Evaluation cutaneous hemangioma is inconsistent [145].
The diagnosis of retinal arteriovenous malfor-

mation is essentially clinical, but fluorescein Genetic Aspects
angiographic studies can be utilized to docu-
ment the vascular pattern. The intracranial arte- Cerebral cavernous malformations (CCM) are
riovenous malformation is best detected by genetically heterogeneous. CCM1 is caused by
magnetic resonance imaging or arteriography mutation in the KRIT1 gene on chromosome
(Fig. 9.6). 7q21-q22; CCM2 is caused by mutation in the
malcavernin gene (MGC4607); and CCM3 is
caused by mutation in the PDCD10 gene [148,
Treatment 149]. It is thought that the proteins encoded by
these genes are involved in endothelial cell func-
The retinal vascular malformations are usually tion [150]. Familial CCM has autosomal-
not amenable to any therapy. Unlike the intracra- dominant inheritance [151].
nial arteriovenous malformations that have a ten-
dency to bleed, the retinal arteriovenous
malformation does not bleed. If neovascular Pathogenesis
glaucoma occurs, symptomatic treatment can be
offered. Because of their location in midbrain, Cavernous hemangiomas are considered to be
intracranial arteriovenous malformations are usu- congenital hamartomas that are composed of
ally inoperable. Embolization may be effective in multiple, thin-walled, dilated, vascular channels
some cases. and surface gliosis [145]. The walls are lined by
normal-appearing endothelium, explaining the
lack of exudation [152].
Prognosis
The retinal vascular anomalies may sometime Clinical Features

lead to vascular occlusions [143] and retinal isch-
emia with development of neovascular glaucoma All patients diagnosed with a retinal cavern-
[144]. Hemorrhages from midbrain hemangio- ous hemangioma should undergo detailed
mas can be fatal. neuroimaging studies even if they are asymp-
tomatic because of their possible association

with cerebral hemangiomas [153]. The diag-
nosis of familial cerebral cavernous malfor-
mations requires histopathologic or imaging
documentation of cavernous hemangiomas in
at least two family members. Bilateral cases
are strongly associated with a positive fam-
ily history. Family members of patients with
bilateral CCM should be screened [154].
etinal Cavernous Hemangioma

R
Retinal lesions appear as grapelike clusters of
blood-filled saccular spaces. The clinical features
are described in detail elsewhere (Chap. 3).
erebral Cavernous Malformation

C
CCM may involve any part of the central ner-
vous system, but supratentorial regions are more
frequently involved than infratentorial ones
[155]. The tumors can occasionally involve the
spinal cord. Seizures, hemorrhages, or progres- Fig. 9.7 Cortical cavernous hemangioma of the CNS
sive focal neurological deficits are common appears in a MRI as a central enhancing core sur-
rounded by a dark ring from previous hemorrhages
manifestations. (arrow)
Diagnostic Evaluation resorbs spontaneously without need for vitrec-

tomy [154].
The ophthalmoscopic features and fluorescein
angiographic findings of retinal cavernous hem-
angiomas are characteristic (Chap. 3). Cavernous Prognosis
hemangiomas of the CNS are best visualized by
MRI, which shows a central enhancing core and In general, retinal cavernous hemangiomas are
a dark ring from previous hemorrhages (Fig. 9.7). nonprogressive. Spontaneous thrombosis and vit-
Because these lesions are venous in origin, they reous hemorrhage are rare complications [145].
are not detected by angiography. Genetic testing is Cavernous hemangiomas of the CNS carry an
available for CCM1-3 [151]. annual risk of 0.25–5% for a clinically significant
hemorrhage [156].
Treatment
Sebaceous Nevus Syndrome
No effective treatment is known, although laser
photocoagulation has been attempted in a few Introduction
cases [145]. Intracranial cavernous hemangi-
oma can be managed by observation, surgical Sebaceous nevus syndrome (of Jadassohn) [157],
excision, or gamma knife radiosurgery depend- also known as Schimmelpenning-Feuerstein-
ing upon location and other considerations Mims syndrome [158, 159], is a distinct clinical
[156]. Vitreous hemorrhage is usually mild and disorder within the spectrum of epidermal nevus
syndrome (of Solomon) [160] characterized by glands, which clinically appears as hypertro-
cutaneous sebaceous nevus and extracutaneous phic and papillomatous. In adulthood, there is a
manifestations [161]. tendency to form benign and malignant skin
tumors, such as sebaceous adenoma and basal
cell carcinoma within the area of the organoid
Genetic Aspects nevus [165].
Sebaceous nevus syndrome is a sporadic disease. Ophthalmic Features

Ocular involvement is observed in about 40% of
cases, with epibulbar choristomas and coloboma
Pathogenesis being the most common [166]. The limbal cho-
ristomas can be simple or complex and usually
The term sebaceous nevus is used to emphasize are dermoid or lipodermoid in nature (Fig. 9.8b)
epidermal and adnexal composition (sebaceous [167, 168] Ophthalmoscopic examination can
glands, sweat glands, and hair follicles) of cuta- reveal coloboma, disc anomalies, or features sug-
neous hamartoma (organoid nevus) and to dif- gestive of intrascleral cartilage (Fig. 9.8c) [169].
ferentiate them from typical melanocytic nevi Intrascleral calcification due to ossification of
[162, 163]. cartilage can also be observed [169, 170].Though
rare, circumscribed choroidal hemangioma has
also been described in linear nevus sebaceous
Clinical Features syndrome [171].
In addition to prominent cutaneous involvement, Neurological Features

neural and ocular manifestations are common in Mental retardation and seizures are the most fre-
sebaceous nevus syndrome (Table 9.12). quent neurological manifestations of sebaceous
nevus syndrome.
Cutaneous Features
Cutaneous lesions are most commonly found Other Manifestations
on the head and neck region and appear as Skeletal abnormalities, cardiovascular defects,
irregular, linear lesions with alopecia and genitourinary defects are occasionally
(Fig. 9.8a). Three stages of age-dependent evo- observed indicating the multisystem nature of the
lution of the organoid nevus have been described sebaceous nevus syndrome [161].
[164]. During infancy, the skin appears atrophic
due to underdevelopment of sebaceous glands.
During the second stage, observed during Diagnostic Evaluation
puberty, there is overdevelopment of sebaceous
The diagnosis of sebaceous nevus syndrome is
Table 9.12 Clinical manifestations of the sebaceous essentially based on clinical findings supported
nevus syndrome by appropriate imaging studies such as magnetic
Organ Feature resonance imaging of the brain. Ophthalmic
Neural Seizures, mental retardation, structural manifestations of intrascleral cartilage/ossifica-
brain defects tion can be demonstrated by ultrasonography or
Ocular Conjunctival/corneal/episcleral choristoma
computed tomography. Cutaneous biopsy may
Lid coloboma
Chorioretinal coloboma prove organoid nature of the nevus with the pres-
Optic nerve coloboma, pit, hypoplasia ence of adnexal components. Other diagnostic
Intrascleral cartilage/bone studies should be ordered based upon suspicion
Cutaneous Midline linear nevus, alopecia, sebaceous of specific organ involvement.
lobules, basal/squamous cell carcinoma
a b
Fig. 9.8 Characteristic manifestations of sebaceous at bone density shows nasal plaque-like lesion in the left
nevus syndrome. Facial and scalp involvement with seba- globe (c). (Reprinted from Traboulsi et al. [170]. With
ceous nevus (a), yellowish orange scleral choristoma of permission from Elsevier)
the superonasal quadrant (b), and computed tomography
associated with sebaceous nevus syndrome is

Treatment due to neurological manifestations of mental
retardation and seizures. In a series of 707 cases
Eyelid and episcleral choristomas can be excised, of sebaceous nevi, malignant neoplasms devel-
and attempts to maximize vision may include oped in 2.5% of lesions. Most of these occurred
corneal grafting, refraction, and amblyopia man- in adults suggesting that surgical excision can be
agement [172]. The organoid nevus should be delayed [174].
removed for cosmetic correction and to prevent
risk of malignant transformation observed in
later stages of life [173]. Ataxia Telangiectasia
Introduction
Prognosis
In 1941, Madame Louis-Bar described a young
The visual prognosis is usually guarded in pres- boy with progressive cerebellar ataxia and ocu-
ence of limbal choristoma, chorioretinal colo- locutaneous telangiectasia [175]. The term
boma, and optic disc anomalies. Morbidity ataxia telangiectasia was proposed by Boder
and Sedgwick in 1958 when they described Table 9.13 Common manifestations of ataxia
telangiectasia
seven cases of familial progressive cerebellar
ataxia, with oculocutaneous telangiectasia and Clinical features Laboratory features
sinopulmonary infections [176]. Other features Progressive Elevated serum alpha-fetoprotein
cerebellar ataxia after 2 years of age
such as lymphoreticular malignancy and Oculocutaneous Elevated plasma
immune dysfunction were not reported until telangiectasia carcinoembryonic antigen
later [177]. Hypotonic facies Low serum antibody levels (IgA,
IgG2, IgE)
Oculomotor apraxia Spontaneous chromosome breaks
and rearrangements (in vitro
Genetic Aspects studies)
Dysplasia of the Increased sensitivity to ionizing
Ataxia telangiectasia (AT) follows an autosomal thymus gland radiation
recessive pattern of inheritance. A gene that Recurrent
pulmonary
causes AT was identified on chromosome 11q22-
infections
23 [178]. Although at least five complementation Susceptibility to
groups have been defined, linkage studies have neoplasia
failed to show linkage heterogeneity. It is now Endocrine
believed that the complementation groups may abnormalities
represent different intragenic mutations or sepa- Progeric changes
rate ataxia telangiectasia genes clustered within
the 11q22.3 region [179]. instability, and hypersensitivity to ionizing
radiation are also important aspects of this disor-
der (Table 9.13) [182].
Pathogenesis
Cerebellar Ataxia
A region of the ATM gene that is homologous to Progressive cerebellar ataxia in early childhood
phosphoinositide-3 kinases mediates cell growth is the hallmark of AT and is present in all cases
signals. A second region homologous to RAD3 [183]. The majority of patients present with
and MEC1 regulates cell cycle explaining diverse truncal ataxia by age 2 years, and almost all
manifestations of AT [180]. develop this neurological sign before age
6 years. Other associated neurological findings
include choreoathetosis, dysarthria, facial hypo-
Clinical Features tonia, and ocular motility disorders. The combi-
nation of oculomotor apraxia with cerebellar
The incidence of AT is about three per mil- ocular motor abnormalities is highly suggestive
lion live births. The minimum frequency of AT of AT [184].
gene mutations in the US white population is
estimated to be 0.0017 [181]. Although AT is Telangiectasia
included by some within the phakomatoses, The telangiectasias have a later onset than the
it has only limited similarity to other disor- ataxia and usually develop by age 6 years; they
ders in this group because it lacks dominant may be absent in some cases. The telangiectasia
inheritance and has a tendency for systemic involves the bulbar conjunctiva and skin of the
hamartomatosis. arms, neck, and shoulder regions.
Ataxia telangiectasia is a childhood neurode-
generative disorder with neural, ocular, and cuta- Other Manifestations
neous manifestations associated with immune Other significant manifestations of AT are dys-
dysfunction. In addition to some of the features plasia of the thymus gland, recurrent pulmonary
outlined below, premature aging, chromosomal infections, susceptibility to neoplasia, endocrine
abnormalities, and progeric changes [185]. mality are common in ATLD secondary to
Lymphoma or leukemia develops in early adult- homozygous W210C MRE11 mutation. Older
hood in about 15% of cases, representing a 1000 patients have nystagmus with abnormalities in
times greater incidence than the general popula- smooth pursuit and vestibular ocular reflex. Eye
tion [186]. movement control systems deteriorate with time.
Ophthalmic features of AT that are not seen in
ATLD patients include conjunctival telangiecta-
Diagnostic Evaluation sia, head thrusting, and manifest strabismus at
distance [191].
The diagnosis of AT is essentially based on clini-
cal findings. The laboratory markers include ele-
vated serum alpha-fetoprotein after 2 years of Neurocutaneous Melanosis
age, elevated plasma carcinoembryonic antigen,
and low serum antibody levels (IgA, IgG2, and Neurocutaneous melanosis (NCM) is a nonfamil-
IgE). In vitro studies on lymphocytes show spon- ial phakomatosis, characterized by multiple and
taneous chromosome breaks and rearrangements. large congenital cutaneous nevi in association
Cultured fibroblasts show increased sensitivity to with meningeal melanosis or melanoma (Fig. 9.9)
ionizing radiation. It is now possible to identify [192]. Rare cases with ocular abnormalities such
disease-causing mutations in more than 80% of as uveal coloboma-like lesions have been
patients with AT including prenatal genotyping reported [193].
[179, 187].
Treatment
AT patients are prone to recurrent sinopulmonary

infections because of immune dysfunction, for
which they need appropriate long-term care.
AT-associated malignancies such as lymphoma
and leukemia require modified chemotherapy
and radiotherapy dosages because of hypersensi-
tivity to radiation and chemotherapy-induced
DNA damage [185, 188].
Prognosis
AT is a progressive disease with poor prognosis

[189]. About one-third of patients die by age
15 years, and survival beyond age of 30 years is
very unusual [190].
Ataxia telangiectasia-like syndrome (ATLD)
is a more recently recognized condition due to
homozygous mutation in MRE11, a gene also
involved in the cellular repair response to double-
Fig. 9.9 Large cutaneous melanocytic nevi of the trunk
stranded DNA breaks; ophthalmic features of in a patient with neurocutaneous melanosis. (Reprinted
ATLD are not well described. Saccadic dysfunc- from Kiratli and Sahin [193]. With permission from
tion without head thrusts and convergence abnor- Taylor and Francis)
Phakomatosis Pigmentovascularis (3) phacomatosis cesiomarmorata (blue spot

with cutis marmorata telangiectatica congeni-
Ota, in 1947, described patients with a com- tal) [195]. Systemic associations with Sturge-
bination of vascular and melanocytic nevi in Weber syndrome or Klippel-Trenaunay-Weber
a Japanese population (phakomatosis pigmen- syndrome can occur. Recent work has shown
tovascularis [PPV]) [194]. Five types of PPV that this is likely caused by activating muta-
are known, but there has been an attempt in tions in GNA11 and GNAQ [196]. Importantly,
the dermatology literature to reclassify this patients with this condition may also develop
order into three subtypes: (1) phacomatosis choroidal melanoma and should be monitored
cesioflammea (one or more blue spots with carefully for this [197]. Ocular involvement
one or more port-wine stains), (2) phacoma- can also include congenital glaucoma, iris
tosis spilorosea (speckled lentiginous nevus of mammillations, and oculodermal melanocyto-
macular type with telangiectatic nevus), and sis (Fig. 9.10) [198].
a b
c d
Fig. 9.10 Phakomatosis pigmentovascularis. Bilateral Ultrasonography B-scan (e, dome-shaped mass) and
cutaneous hemangioma of Klippel-Trenaunay-Weber A-scan (f, low internal reflectivity) and ICG (g, hypofluo-
syndrome (a) with bilateral scleral hyperpigmenta- rescence with intrinsic vessels) were suggestive of choroi-
tion (b, c, ocular melanocytosis) and choroidal mass in dal melanoma rather than hemangioma. Uveal melanoma
the right eye causing exudative retinal detachment (d). was confirmed upon enucleation
e g
0ms 10ms 20ms 30ms
I ntracranial Cavernous Angiomas debate regarding the treatment modality of

(Cavernomas) choice.
The two most important risk factors for hem-
Cavernomas angiomas have an estimated preva- orrhage are previous hemorrhage and brainstem
lence of 0.16–0.5%. They are uncommonly seen location [151]. Another important risk factor is
in neurosurgical practice because they can occa- found in young women wishing to become preg-
sionally rupture [151]. Recent developments in nant. The hormonal state of pregnant women
neurosurgical technique and microbiology have is such that endothelial cell proliferation may
brought greater insight into the treatment and increase the risk for hemorrhage substantially.
molecular pathogenesis of cavernoma. Familial The clinical presentation of these lesions is
cases can occur due to mutations in the genes highly variable, ranging from an incidental find-
CCM1 (KRIT1), CCM2 (MGC4607), and CCM3 ing on neuroimaging to discovery at autopsy after
(PDCD10) [151]. There are a number of contro- fatal hemorrhage. The most common symptom of
versies regarding management of these lesions. cavernous malformation is seizure followed by
These include risk factors faced by the patient, focal neurological deficits, acute hemorrhage,
controversy over the importance of resection, and and headache.
Asymptomatic lesions are generally observed an NF1-associated neurofibroma. Genes Chromosom

Cancer. 1999;24:283–5.
without surgical excision [151]. In cases requir- 11. Serra E, Rosenbaum T, Winner U, et al. Schwann cells
ing surgical excision, the well-circumscribed harbor the somatic NF1 mutation in neurofibromas:
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Ocular Paraneoplastic Diseases
10
Ilya Leskov and Arun D. Singh
Introduction specific epitope on a given antigenic protein.

With time, a process called “epitope spreading”
Paraneoplastic retinopathies are presently con- occurs, wherein antibodies cross-react with a dif-
sidered as autoimmune conditions (Table 10.1). ferent epitope on the same protein [5]. These sub-
Secreted tumor antigens are internalized by antigen- sequently generated antibodies may be the ones
presenting cells that direct the antitumor humoral that ultimately lead to retinal pathology. This
response, stimulating the production of antitumor explains why some individuals with antibodies
antibodies. Some of these antibodies may cross- against cancer-associated retinopathy targets,
react with similar or identical antigens in the retina, such as recoverin, enolase, and carbonic anhy-
resulting in retinal degeneration. Recoverin was the drase II, do not develop retinopathy [5–7].
first such identified antigen, as characterized by Pathogenic antibodies are able to penetrate
Thirkill and associates [1, 2]. Since then, numer- retinal tissues and cross cell membranes to
ous other retinal antigens have been proposed, enter cells that express their targets [5]. Their
including proteins in photoreceptor cells that medi- effect depends on the function of their target.
ate phototransduction cascade (arrestin, guanylate Recoverin, for example, functions in light
cyclase-activating protein, transducin, rhodopsin), and dark adaptation by regulating rhodopsin
as well as proteins in retinal bipolar and ganglion phosphorylation and dephosphorylation in a
cells involved in glycolysis (enolase, aldolase, glyc- calcium-dependent manner [8]. Once internal-
eraldehyde-3-phosphate dehydrogenase) and stress ized by photoreceptors, anti-recoverin antibod-
and homeostatic responses (heat shock proteins, ies lead to increase in intracellular calcium
carbonic anhydrase) [3–5]. and activation of mitochondrial caspase 3 and
It is thought that an initial antitumor humoral caspase 9-driven apoptosis, ultimately result-
response produces antibodies that react to a ing in retinal degeneration [9, 10]. Anti-enolase
antibodies bind to Muller cells and ganglion
cells, inactivating their target enzyme, inhib-
I. Leskov iting glycolysis, and inducing apoptosis [11].
Department of Ophthalmic Oncology, Cole Eye
Institute, Cleveland Clinic Foundation, Anti-carbonic anhydrase II antibodies impair
Cleveland, OH, USA their target enzyme as well, resulting in lower
A. D. Singh (*) intracellular pH and increase in intracellular
Department of Ophthalmic Oncology, calcium, ultimately reducing cell viability [12].
Cole Eye Institute, Cleveland Clinic, Antibodies against transient receptor poten-
Cleveland, OH, USA tial channel protein 1 (TRMP1) expressed

148 I. Leskov and A. D. Singh
Table 10.1 Clinical features of paraneoplastic retinopathies

Feature CAR MAR BDUMP
Symptoms Bilateral visual loss Near normal acuities Severe visual loss
Positive visual phenomenon Normal color vision Cutaneous/mucosal focal
Nyctalopia Normal central visual fields melanocytic proliferation
Fundus exam Vessel attenuation, Majority have normal appearance. Few Multiple elevated uveal
chorioretinal atrophy, optic have vascular attenuation, RPE changes, melanocytic tumors
atrophy and vitreous cells Exudative retinal
detachment
Visual field Central/paracentral scotoma Paracentral scotoma Central/paracentral
scotomas
ERG findings Depressed scotopic and “Negative” ERG Depressed scotopic and
photopic response photopic response
Associated Lung carcinoma (small cell) Cutaneous melanoma Small cell carcinoma and
malignancy Gynecological carcinoma others
Breast carcinoma
Antibodies Anti-recoverin, Rod bipolar “ON” cells None
Anti-enolase
Anti-65-kDA
Heat shock cognate protein
70
Prognosis Progression to severe visual Progression to severe visual loss Progression to severe
loss visual loss
CAR cancer-associated retinopathy, MAR melanoma-associated retinopathy, BDUMP bilateral diffuse uveal melano-
cytic proliferation
on ON bipolar cells are associated with reti- carcinoid tumor of the small bowel, seminoma,
nopathy in patients with cutaneous melanoma thymoma, and Langerhans cell histiocytosis
(MAR). These antibodies target an intracellular [16–23]. Analysis of a series of 209 patients with
sequence of TRMP1; their intracellular uptake CAR showed that disease onset generally occurs
and accumulation result in bipolar cell dysfunc- after age 45, with average age of 65; women were
tion characteristic of MAR. [13, 14] It is likely affected twice as frequently as men [21]. Despite
that aberrant autoantibodies targeting other improved recognition of the disorder and an
retinal antigens result in the apoptosis of cells expanding appreciation of its associations, there
expressing their targets in similar fashion. remains much to understand of the underlying
pathogenesis and treatment of CAR.
Cancer-Associated Retinopathy
Introduction
Antibodies found to be associated with CAR
The first published report of photoreceptor degen- include ones directed against the phototransduc-
eration occurring as a result of a remote cancer tion protein recoverin, the glycolytic enzymes
was a series of three patients with small cell lung enolase and glyceraldehyde 3-phosphate dehy-
cancer (SCLC) by Sawyer et al. in 1976 [15]. drogenase, tubby-like protein 1 (TULP1) that
While it remains most commonly associated with participates in transport of phototransduction
SCLC, CAR has also been associated with hema- components, heat shock cognate protein 70, and
tologic malignancies, gynecologic and breast carbonic anhydrase II, among others [24].
carcinoma, and less commonly non-small cell Aberrant expression of recoverin has been
carcinoma of the lung, laryngeal, bladder, thy- demonstrated in a number of cancer cell lines
roid, prostate, colon, and hepatocellular cancer, and is thought to play a role in cell proliferation
10 Ocular Paraneoplastic Diseases 149
[25]. Tumor-expressed recoverin is known to be iritis. Posterior segment findings predominate

antigenic and anti-recoverin antibodies are com- and include narrowing of retinal vessels, chorio-
monly identified in patients with various cancers retinal atrophy, and optic nerve atrophy. Vitritis,
[26, 27]. Systemic administration of recoverin in periphlebitis, and arteriolar sheathing occur later
a rat model was found to result in immunization in the disease course [34].
and subsequent retinal degeneration [28]; and
intravitreal injection of anti-recoverin antibod-
ies in rats has also been shown to cause retinal Diagnostic Evaluation
degeneration [29]. Interestingly, intravenous
anti-recoverin antibodies given to mice were Assessment of retinal function using Goldmann
not able to cross the blood-retina barrier, and or Humphrey visual fields, Farnsworth color
no retinal degeneration occurred [30]. Vascular assessments, and electroretinography (ERG) is
endothelial growth factor has been investigated important for establishing the diagnosis. Visual
as a potential mediator of blood-retina barrier field testing can manifest variable defects such
modification, though its role remains unclear as central, paracentral, or arcuate/ring scoto-
[31]. It appears that the cellular immune system mas and generalized field depression. However,
may provide the additional component neces- the most common finding is constriction of
sary to induce antibody-related damage. Maeda central 20 degrees of the visual field [35].
et al. demonstrated that, in addition to immuni- Electroretinographic studies are helpful both
zation with recoverin, inhibition of the cytotoxic in the confirmation of the diagnosis, especially
T lymphocyte antigen 4 pathway (thus block- when the clinical findings are subtle (Fig. 10.2).
ing inhibition of T cell activation) is necessary The classic picture seen with CAR includes
to produce CAR-like retinal degeneration in a suppression of both the photopic and scotopic
murine model [32]. responses [36], though the profile of loss may
correspond to the underlying antibody—diffuse
rod and cone loss in anti-recoverin retinopathy
Clinical Features and more central cone loss in anti-enolase reti-
nopathy [33].
Symptoms Another critical component of the evaluation
Cancer-associated retinopathy is characterized of patients with suspected CAR is a serum assay
by painless progressive visual loss over weeks to for anti-retinal antibodies, which can be per-
months, often accompanied by early complaints formed by commercial or academic laboratories.
of decreased near vision, and positive visual phe- Unfortunately, serum antibody testing is fraught
nomena such as shimmering lights (Fig. 10.1). with not only a lack of standardization between
While there is much overlap, the underlying laboratories but also the heterogeneity of autoan-
antigen may predict a distinctive profile of symp- tibodies found in patients [24]. Not all patients
toms. Symptoms of anti-recoverin-related reti- with suspected CAR have identifiable anti-retinal
nopathy reflect widespread retinal dysfunction, antibodies, while a significant number of patients
including nyctalopia, photopsia, and peripheral with non-neoplastic autoimmune retinopathy
and pericentral scotoma, whereas anti-enolase have anti-retinal antibodies [37]. Though, as
retinopathy may more commonly cause hemera- noted above, these may bind to different epitopes
lopia, color disturbance, photopsia, and variable of their target. Moreover, some patients may have
central field defects [33]. multiple antibodies, but the offending antibody
is not always identifiable [37]. The discovery of
Signs anti-recoverin antibodies, however, should raise a
Early in the course, the eye may appear to be high level of suspicion for malignancy, as several
entirely normal. Anterior segment findings have studies have shown these to be strongly associ-
rarely been reported in cases of CAR, except for ated with CAR [37].
a1 a2
b1 b2
Right eye Left eye

Field view Field view
c1 c2
500nV
500nV
0 80ms
0 80ms
Fig. 10.1 A 61-year-old white male presented to the OU, and a Goldmann visual field showed peripheral con-
neuro-ophthalmology service in consultation for bilateral striction with the I-4 targets OU (a). Dilated fundus exam
progressive decrease in vision that started approximately showed mildly attenuated retinal arterioles but was other-
1 year prior to presentation. He saw an ophthalmologist wise unremarkable (b). There was no sheathing noted on
1 month prior to his presentation who noted mild sheath- fundus examination. Multifocal ERG revealed severe
ing of his retinal vessels without anterior uveitis or vitritis. attenuation of a- and b-waves centrally OU (c). Serum
Past medical history was significant for asthma, and the anti-retinal antibody tests showed the presence of anti-α
patient had previous hernia repair and sinus surgery. He enolase antibodies with staining of the inner nuclear layer
denied diabetes, known malignancies, or autoimmune dis- on immunohistochemistry. The patient was diagnosed
eases. On ophthalmic examination, his best-corrected with probable cancer-associated retinopathy. Further
visual acuity was 20/80 OD and 20/40 OS. IOP was 19 workup revealed the presence of a peripheral lung nodule
OU, and pupils were equal and reactive without an affer- whose biopsy showed the presence of signet-ring cell car-
ent pupillary defect. His extraocular movements were full cinoma. (Courtesy of Gregory S. Kosmorsky, MD)
Stimulus Normal Subject
Dark-adapted −
2.0 log cd s/m2
Dark-adapted
0.5log cd s/m2
Light-adapted
0.5 log cd s/m2
31 Hz Flicker
0.5 log cd s/m2
Fig. 10.2 A 67-year-old man with a known history of two eyes of the patient were averaged together.
lung cancer presented with halos in both eyes. Extinguished ERG responses in the patient were sugges-
Electroretinograms recorded from a normal control sub- tive of cancer-associated retinopathy. (Courtesy Neal
ject and from the patient. Responses recorded from the Peachey, PhD, Cleveland, Ohio)
Retinal imaging may be normal or nonspecific

to CAR. Retinal vein leakage and perivascular Differential Diagnosis
window defects have been reported on fluorescein
angiography [38]. Spectral domain OCT usually Cancer-associated retinopathy must be distin-
shows loss of outer retinal structures, including guished from other paraneoplastic ocular dis-
the outer nuclear layer, the external limiting mem- eases, including retinopathy associated with
brane, and the ellipsoid layer, as well as the appear- melanoma (MAR) and paraneoplastic optic
ance of cystoid and schisis-like changes [39–41]. neuropathy, as well as non-paraneoplastic auto-
immune retinopathy, hereditary retinal dis- systemic steroids have been published [47–50].
ease, and other causes of retinal degeneration. As increased intracellular calcium has been
Furthermore, optic neuropathies due to adverse implicated in the pathogenesis of CAR, calcium
effects of chemotherapeutic agents such as vin- channel blockade has shown benefit in experi-
cristine, optic nerve infiltration by a primary car- mental models, though success in humans has
cinoma, or anterior ischemic optic neuropathy yet to be reported [51]. While it is generally
must be ruled out. held that systemic management is required, local
treatment with either intravitreal or sub-Tenon
steroid injections may be beneficial in some
Treatment patients [45, 52].
Though numerous modalities have been inves-

tigated including steroids, immunomodulation, Prognosis
intravenous immunoglobulin (IVIG), plasma-
pheresis, and calcium channel blockers, the The visual prognosis with CAR is generally
visual improvement after treatment for CAR— very poor; without treatment vision may dete-
if any—is generally modest and often transient. riorate to light perception or no light perception.
Early diagnosis is critical, since once photore- In a retrospective review, severe deterioration in
ceptor degeneration has begun, treatment may vision (less than 20/200) was found in 47% of all
at best stabilize vision. Anti-retinal antibody patients [35].
titers may be useful in guiding treatment, as
some authors have reported successful manage-
ment using increased titers as an indication to Melanoma-Associated Retinopathy
resume therapy [37, 42]. Unfortunately, treat-
ment of the primary tumor, including the use of Introduction
chemotherapy, radiotherapy, and local excision
of the primary tumor, is rarely effective against The first case of remote ocular disease occur-
CAR [16], with only rare reports describing ring in the setting of metastatic cutaneous mela-
improvement in retinal appearance on OCT and noma was presented by Gass in 1984, when he
recovery of visual function following systemic described a patient with acute vision loss, uveitis,
chemotherapy for the patient’s primary malig- and large areas of depigmentation of the choroid
nancy [43, 44]. [53]. Melanoma-associated retinopathy was even-
Intravenous high-dose methylprednisolone tually coined as a distinct clinical entity when
and less commonly oral steroids are generally Berson showed in1988 that this night blindness
the first-line approach to management of CAR, was a paraneoplastic phenomenon [54]. The syn-
either alone or in combination with systemic drome is characterized by nyctalopia, shimmer-
immunomodulator therapy. Ferreyra and col- ing photopsias, and an unremarkable or atrophic
leagues reported an improvement in visual acu- fundus exam in a patient with metastatic cutane-
ity or expansion of visual fields in a series of ous melanoma and characteristic ERG findings.
CAR patients treated with combination therapy Unlike CAR, which may be diagnosed before or
of prednisone, azathioprine, and cyclosporine after the identification of the underlying malig-
[45]. Intravenous immunoglobulin was success- nancy, MAR is nearly always diagnosed when
ful in improving visual acuity or visual fields in metastatic disease is already evident. In a review
a small case series [46]. Single-case reports of of the cases of MAR published in the literature,
successful preservation of vision with alemtu- only two patients presented prior to any diagno-
zumab, improvement of vision with rituximab, sis of melanoma and six before metastases were
and with plasmapheresis in combination with found [16].
Etiology and Pathogenesis Diagnostic Evaluation
Similar to CAR, patients with MAR have anti- As with other paraneoplastic retinopathies, initial
bodies toward tumor antigens which cross-react diagnostic evaluation should consist of Goldmann
with antigens on retinal cells, most commonly or Humphrey visual fields, Farnsworth color
targeting the rod bipolar cell [55]. As with assessments, and ERG. Visual field testing can
CAR, numerous antibodies have been identified, reveal mid-peripheral defects or peripheral field
including S-arrestin, recoverin, α-enolase, aldol- depressions. Melanoma-associated retinopathy
ase A, aldolase C, and rhodopsin, among others manifests typical ERG abnormalities, including
[56, 57]. More recently, autoantibodies specific absent or reduced b-waves even after dark adap-
to the TRPM1 cation channel of ON bipolar cells tation with preserved a-waves [58]. A positive
have been described [13]. This selective damage history of cutaneous malignant melanoma and
of bipolar and Mueller cells produces a negative- circulating antibodies directed toward human
appearing scotopic ERG response, termed the bipolar cells support the diagnosis (Fig. 10.3).
“negative ERG” [36].
Differential Diagnosis
Clinical Features
Melanoma-associated retinopathy must be differ-
The vast majority of patients with MAR are male, entiated from similar clinical presentations with an
most often with the established diagnosis of cuta-
neous melanoma, though it may also occur with
choroidal or ciliary body melanoma [57, 58].
Symptoms
The clinical features of MAR are similar to
that seen in other paraneoplastic retinopathies.
Patients typically report shimmering, flickering
photopsias, peripheral scotomas, acute-onset
night blindness, and slowly progressive visual
loss [58, 59]. Subclinical MAR as detected by
ERG, peripheral visual field evaluation, and
nyctometry appears to be more common than
previously suspected in patients with cutaneous Fig. 10.3 A 64-year-old man presented with photopsia,
melanoma [60]. difficulty with night vision, and reduced peripheral visual
field in both eyes of 3-month duration. He had been recently
diagnosed with malignant melanoma of the maxillary
Signs
sinus. The corrected visual acuity was 20/20 in both eyes.
Patients typically have near normal visual acu- Results of the anterior segment and fundus examination
ities, color vision, and central visual fields were normal in both eyes. An electroretinogram showed
unlike CAR patients who manifest more severe marked reduction in the b-wave amplitude under scotopic
testing conditions to a bright flash. Indirect immunofluores-
deficits at presentation [59]. Few patients with
cence was performed on cryosections of unfixed human
MAR manifest fundus changes. In a series of retina using serum and IgG from the patient. Fluorescein
34 patients with proven MAR, 44% of patients isothiocyanate-labeled antihuman IgG and IgM were used
had normal findings at presentation, 30% had as secondary antibodies. A weak but specific labeling of
bipolar cells was observed (arrow). Patient’s visual status
vascular attenuation, and 28% had RPE changes.
remained stable for the next 12 months when he died from
Vitreous cells were present in 30% patients, and metastatic disease. (Reprinted from Singh et al. [111]. With
23% had optic disc pallor [59, 61]. permission from Elsevier)
electronegative ERG, such as congenital station- rosensory retina has been described, although
ary night blindness (CSNB) [62], juvenile retinos- this entity may actually have been alluded to
chisis [63], and non-ischemic central retinal vein by Gass [61, 69–71]. In 2001 Borkowski et al.
occlusion [64]. Systemic treatment for melanoma described two cases of a MAR-like syndrome
with interferon may also cause a retinopathy, with unusual fundus features [61]. In the first
though this is easily distinguished by its features case, there were oval, white lesions at the level
of intraretinal hemorrhage and cotton wool spots of the RPE, and in a second, there were scat-
[65]. While eye history and exam can help distin- tered, well-circumscribed, atrophic lesions in
guish some of these entities, ancillary testing with the posterior pole and mid-periphery [61]. Other
ERG and serum antibody testing establish the groups have reported MAR-like presentations
diagnosis. Congenital stationary night blindness with multiple serous retinal and RPE detach-
can be distinguished on ERG from MAR since ments [69, 71, 74, 75]. In 2005 Sotodeh et al.
blue cones are typically spared in CSNB. reported two cases of a MAR-like retinopathy
with serous macular detachments and a third
case with small, yellow, curvilinear, vitelliform
Treatment lesions [73]. This group was the first to use the
term paraneoplastic vitelliform retinopathy.
The key to management is early detection, since Since that time, others have also described simi-
MAR causes irreversible destruction of bipolar lar appearing cases of paraneoplastic vitelliform
and Mueller cells. The treatment is similar to CAR retinopathy with multiple serous retinal detach-
in that there is no established treatment paradigm; ments [70, 72, 76, 77].
however there is more deference given to cyto-
reduction, either by means of metastasectomy,
or chemotherapy and radiation [66]. Intravenous Etiology and Pathogenesis
immunoglobulin is also frequently employed,
often in combination with cytoreduction of the Retinal autoantibodies most commonly directed
primary tumor by radiation, plasmapheresis, and against bipolar cells, carbonic anhydrase II, inter-
steroids [59, 67, 68]. Unfortunately, the results photoreceptor retinoid-binding protein (IRBP),
of treatment are generally unimpressive; a meta- bestrophin, α-enolase, myelin basic protein, and
analysis of the literature found that only 4% in rod outer segment proteins and transient receptor
MAR had visual improvement or improvement in potential M1 cation channels of retinal ON bipo-
fundus appearance after treatment [16]. lar cells have been reported [78].
Prognosis Clinical Features
Visual loss in MAR is progressive due to the decline Symptoms

in retinal function seen late in the disease course. Males and females are equally affected [76]. The
In a review of 34 patients with MAR, there was a majority have metastatic cutaneous melanoma,
significant decline in acuity with only ten patients while less than a third have metastatic uveal mel-
retaining visual acuity better than 20/60 [59]. anoma. Most individuals reported some degree of
visual loss, nyctalopia, and photopsia.
Paraneoplastic Vitelliform Signs

Retinopathy The fundus appearance in paraneoplastic vitel-
liform retinopathy is characterized by multiple
Introduction large, round, white to yellow subretinal depos-
its predominantly affecting the macula and may
More recently, a MAR-like retinopathy with show areas of shallow serous retinal detachment
associated detachments of the RPE and neu- [79]. (Fig. 10.4).
a1 a2
HRE RPE
c
Anti-enolase Ab
(control)
Specific for RPE
CAll
Fig. 10.4 Fundus appearance of paraneoplastic vitelli- (CAII) in retina and RPE (c). Postmortem microscopic
form retinopathy in an 80-year-old man with metastatic examination showed focal retinal edema (asterisks) and
cutaneous melanoma (a-1 right eye, a-2 left eye). Spectral loss of nuclei in the inner nuclear layer, likely without
domain optical coherence tomography revealed high- bipolar cell preservation. (Hematoxylin and eosin (origi-
resolution imaging of all retinal layers and confirmed the nal magnification × 200)) (d). Transmission electron
location of these lesions in the deep retina between the micrograph showing cross section of the inner nuclear
outer nuclear layer and the RPE (b). Western blot of the layer illustrating the damage targeted by autoantibodies.
patient’s serum tested against human retinal (HRE) pro- Signs of deterioration include stacked filaments (arrow-
teins and human retinal pigment epithelium (RPE) pro- heads), vacuoles/phagosomes (arrows), and disintegrated
teins revealed that the serum had a high titer of retinal mitochondria (concave arrowhead) (e). (Reprinted from:
autoantibodies directed against carbonic anhydrase II Aronow et al. [76]. With permission from Elsevier)
Treatment
d
There is no known effective treatment. There are
few reports describing treatment for paraneoplas-
tic vitelliform retinopathy, though prednisone
may reduce subretinal fluid accumulation with a
corresponding improvement in visual acuity [80].
The role of more aggressive immunosuppression
in treatment of such cases is not known [45].
Prognosis
Most individuals succumb to metastatic disease

e within months of diagnosis [76].
ilateral Diffuse Uveal Melanocytic

B
Proliferation (Paraneoplastic
Melanocytic Proliferation)
Introduction
Bilateral diffuse uveal melanocytic prolifera-

tion (BDUMP) is a rare paraneoplastic disorder
which causes bilateral painless visual loss with
diffuse uveal thickening and pigmentary changes
of the fundus in patients with systemic carcino-
mas. Since its original description by Machemer
in 1966 [81] and subsequently Barr in 1982 [82],
approximately 60 cases have been published [83–
85]. Often, the primary carcinoma is unknown at
Diagnostic Evaluation presentation, and recognition of the characteris-
tic ocular findings prompts a systemic workup.
Visual field testing has yielded variable results The primary tumor may arise from numerous
from normal to cecocentral scotomas [70, 73]. sites; however, gynecological neoplasia and lung
Color vision testing may reveal errors along and pancreatic cancer predominate [83]; other
the tritan axis on Farnsworth D-15 testing sites including the colon, gallbladder, breast, and
[70]. Reduction in both the a-wave and b-wave esophagus have been reported [16, 85].
amplitudes for both scotopic and photopic
ERG testing is common. EOG may be normal
or may show a pathologically reduced Arden Etiology and Pathogenesis
ratio [70, 76]. Paraneoplastic vitelliform reti-
nopathy may be mistaken for Best’s disease, The exact pathogenesis of BDUMP remains
RDS/peripherin spectrum dystrophies, and unknown. Histopathology shows melanocytic
Harada syndrome. infiltration composed predominately of benign
nevus cells with few mitotic figures in the uvea Mucosal involvement may even be widespread,
and the skin [86]. Since the proliferation of mela- with pigmentation of the oral mucosa and lips,
nocytes is not limited to the uvea, paraneoplastic penis, and rectum [86]. Similarly, the acquired
melanocytic proliferation may be a more descrip- cutaneous pigmentation appears to be site non-
tive terminology [86]. It is believed that produc- specific with the head, neck, shoulder, and vul-
tion of hormonal or other oncogenic stimulus val involvement [83]. Gass established the five
by the primary carcinoma causes activation and cardinal ocular signs associated with the diag-
proliferation of preexistent nevus cells within the nosis of BDUMP: (1) the typical fundus pattern
uveal tract, mucosal membranes, and the skin. found in BDUMP consists of multiple elevated
Miles et al. demonstrated that human melano- red round patches at the level of the retinal pig-
cytes proliferate when exposed to sera or plasma ment epithelium, (2) multifocal pattern of early
of patients with BDUMP; this so-called “cultured hyperfluorescence corresponding to the patches,
melanocyte elongation and proliferation” (CMEP) (3) pigmented and nonpigmented uveal melano-
factor was then localized in the IgG fraction of the cytic tumors and diffuse thickening of the uvea,
sera [87]. In a follow-up study, sera from patients (4) coexistent exudative retinal detachment, and
who had undergone plasmaphoresis failed to stim- (5) the rapid development of cataracts [92]. Other
ulate melanocyte proliferation, suggesting this as slit lamp findings may include anterior chamber
a promising treatment modality [88]. Indeed, there cell, vitreous cell, pigmented iris patches, and
have been several reports of patients whose visual signs of ciliary body enlargement such as dilated
loss was stabilized and even reversed following this episcleral vessels, shallow anterior chamber, and
treatment [84, 88, 89]. RPE atrophy in BDUMP iridodonesis.
is poorly understood. Some have speculated that
the increased metabolic demand of proliferating
melanocytes leads to RPE hypoxia, while others Diagnostic Evaluation
have proposed that the RPE atrophy occurs as a
separate paraneoplastic process [90, 91]. As with other paraneoplastic ocular disorders,
initial diagnostic evaluation should consist of
Goldmann or Humphrey visual fields, ERG, and
Clinical Features color assessments. Additionally, ultrasonography
may be useful in demonstrating peripheral serous
The mean age at diagnosis of BDUMP syndrome detachments and choroidal thickening, though
is 64 years and it has no sex predilection [83]. these are sometimes subclinical [83]. ERG stud-
Ovarian cancer and lung or pancreatic cancer are ies show a nonspecific pattern of decreased
the most common underlying malignancies in cone and rod responses. Fundus autofluores-
females and males, respectively [83]. cence of the reddish patches show patchy hypo-
autofluorescence; correspondingly, fluorescein
Symptoms angiography demonstrates early window defect
In half of the reported cases, the ocular symp- hyperfluorescence due to focal destruction of the
toms manifest before the diagnosis of an under- pigment epithelium with sparing of the chorio-
lying malignancy. Patients typically present with capillaris [93]. In late frames, there is marked
unexplained, acute to subacute bilateral vision choroidal hyperfluorescence with patches of
loss (Fig. 10.5). hypofluorescence [92]. Spectral domain OCT
confirms patchy RPE atrophy in areas of hypo-
Signs autofluorescence, with adjacent RPE thickening,
Systemic examination may reveal focal cutane- photoreceptor loss, and occasionally mild sub-
ous and mucosal melanocytic proliferation [86]. retinal fluid [93].
a b
c d
Fig. 10.5 A 56-year-old woman presented with progres- fluorescence corresponding to the distribution of the
sive deteriorating vision in both eyes for the last 6 months. orange pigment and multifocal patchy hyperfluorescence
The onset of visual symptoms coincided with the diagno- in the right eye (c). The angiographic findings were simi-
sis of large cell carcinoma of lung. She was not known to lar but were more pronounced in the left eye (d). The
have metastasis and was receiving chemotherapy. The patient had recently noticed new-onset pigmented lesions
corrected visual acuity was 20/40 in the right eye and on her forearms and thighs for the last few months (e).
20/60 in the left eye. Anterior segment examination was Histopathologic evaluation of one of the cutaneous lesions
unremarkable. On ophthalmoscopic examination, the cho- showed confluent proliferation of cytologically atypical
roid was diffusely thickened in both eyes (a-right eye, melanocytes in the basal layers of the epidermis with focal
b-left eye). The choroid was also markedly hypermela- extension into the mid-epidermis (f). Patient’s visual sta-
notic with scattered areas of orange pigmentation. The tus worsened for the next 6 months when she died from
choroidal thickening was confirmed by B-scan ultraso- metastatic disease. (Reprinted from Singh et al. [86]. With
nography. Fluorescein angiographic studies showed hypo- permission from American Medical Association)
stabilizing or even improving the vision in three

f
patients [84, 88, 89].
Prognosis
Since BDUMP is often the first manifesta-

tion of an occult carcinoma, early diagnosis is
important for initiating appropriate therapy and
prolonging survival. Unfortunately, the iden-
tification of BDUMP typically heralds a poor
prognosis, with death typically occurring within
Fig.10. 5 (continued)
2 years. There have been no reported cases of
metastasis from the choroidal lesions found in
Differential Diagnosis BDUMP, though this may reflect the relatively
short survival of most patients [83]. Visual acu-
Bilateral diffuse uveal melanocytic proliferation ity loss is typically profound, with a majority of
should be distinguished from other inflamma- patients reaching hand motion or light percep-
tory or neoplastic disorders which cause multifo- tion [83].
cal or diffuse cellular infiltration of the choroid.
These can be separated into two categories based
on the presence or absence of pigmented choroi- Paraneoplastic Optic Neuropathies
dal tumors. Idiopathic uveal effusion syndrome,
large cell lymphoma, metastatic carcinoma, leu- Introduction
kemia, multifocal and diffuse choroiditis, pos-
terior scleritis, and benign reactive lymphocytic Paraneoplastic optic neuropathies (PON) tend to
hyperplasia can mimic BDUMP prior to the occur within the clinical spectrum of cerebellar
emergence of multifocal pigmented choroidal and brainstem paraneoplastic disorders though on
tumors. Metastatic melanoma to the uvea and rare occasion may occur in isolation [95]. These
multiple choroidal nevi can also resemble the optic neuropathies are most typically found in
multifocal pigmented choroidal tumors observed association with small cell lung cancer, but have
in BDUMP syndrome. also been reported in non-small cell lung cancer,
Hodgkin’s and non-Hodgkin’s lymphoma, neuro-
blastoma, bronchial carcinoma, nasopharyngeal
Treatment carcinoma, thymoma, prostate cancer, papillary
renal cell cancer, and various neuroendocrine
As with other paraneoplastic retinopathies, tumors [16, 96–99].
BDUMP has no effective treatment. Early expe-
rience with corticosteroids and ocular external
radiotherapy did not prevent the progression of Etiology and Pathogenesis
the disease [94]. Similarly, vitrectomy, silicone
oil injection, and panretinal photocoagulation As with CAR and MAR, cross-reacting antitu-
all failed to prevent the retinal detachments seen moral and anti-neuronal antibodies have been
in the late stages of BDUMP [92]. Intravitreal identified. Antibodies to collapsin response-
anti-vascular endothelial growth factor ther- mediating protein-5 (CRMP-5) are the best
apy has also been tried unsuccessfully to treat characterized and most commonly identified,
subretinal fluid involving the macula [93]. though there have been reports of other anti-
Recently, there have been case reports of plas- bodies [99, 100]. Presumably reaction with the
mapheresis or plasma exchange as a means of CRMP-5 antigen results in the pathologic find-
ings of inflammatory cell infiltration, demy- Differential Diagnosis

elination, or both [100].
Paraneoplastic optic neuropathy should be distin-
guished from paraneoplastic retinopathy; acute
Clinical Features ischemic optic neuropathy; neoplastic, infectious,
or inflammatory infiltration of the optic nerve;
Symptoms and demyelinating disease such as neuromyelitis
Neurologic symptoms may precede or follow optica and multiple sclerosis. Additionally, dis-
the ocular manifestations of the syndrome. cerning paraneoplastic optic neuropathy from an
Patients present with unilateral, subacute, pain- adverse effect of a chemotherapeutic agent may
less vision loss that progresses over weeks to be a difficult diagnostic challenge.
months, often with loss developing in the fel-
low eye. Additional ophthalmic symptoms
may include blurred vision, tunnel vision, and Treatment
photopsias.
Treatment of the underlying malignancy with
Signs excision, radiation, and chemotherapy coupled
Decreased visual acuity on Snellen assessment is with corticosteroids may improve visual acu-
nearly universally present, and unless the optic ity and visual field defects [16]. Sometimes the
nerve involvement is symmetric, the patient will improvement is substantial, while in other cases
have a relative afferent pupillary defect. Exam the vision continues to decline despite all treat-
may disclose a normal fundus and optic nerve, ment efforts [102, 103].
disc pallor or papilledema, as well as vitritis and
retinitis [16]. In addition, patients can present
with neurological findings of encephalomyelo- Prognosis
radiculopathy which can include mental status,
cranial nerve, motor, autonomic, and movement The prognosis of paraneoplastic optic neuropathy
disorders [100]. is quite mutable—patients may have significant
recovery of visual function or be left with sig-
nificant visual loss. The fact that nearly complete
Diagnostic Evaluation visual recovery can follow successful treatment
of the underlying cancer emphasizes the impor-
Color plates and visual field testing are useful tance of early diagnosis [102, 104–106].
complements to afferent pupillary defect test-
ing in the clinic. Electrophysiology, unless a
combined retinitis is present, is typically normal psoclonus and Paraneoplastic Eye
O
and useful in excluding CAR and MAR [101]; Movement Disorders
visual-evoked response may be delayed [100].
Visual fields may show a range of defects, but Paraneoplastic eye movement disorders may
peripheral constriction and cecocentral scotomas arise from involvement of the cerebellum and
are particularly common [100]. Cerebrospinal brainstem or result from direct interaction with
fluid analysis often shows mild to moderate lym- cellular receptors, such as in Lambert-Eaton
phocytosis and elevated protein levels but no syndrome. Opsoclonus is part of a larger group
evidence of malignant cells. While antibodies to of ocular disorders caused by paraneoplastic
CRMP-5 are a useful component of diagnostic cerebellar degeneration. Ocular findings often
testing and may be demonstrated in the serum or are abnormal, including horizontal or vertical
cerebral spinal fluid, they are not required for the nystagmus, dysconjugate gaze, ocular dysmet-
diagnosis [99, 100]. ria, and opsoclonus. In opsoclonus the clinical
picture is referred to as “dancing eyes” due to 10. Adamus G, Webb S, Shiraga S, et al. Anti-recoverin
antibodies induce an increase in intracellular calcium,
the rapid ocular movements [107]. Lung cancer leading to apoptosis in retinal cells. J Autoimmun.
and neuroblastoma are the most common malig- 2006;26(2):146–53.
nancies reported with opsoclonus in adults and 11. Magrys A, Anekonda T, Ren G, et al. The role of
children, respectively [108], but it has also been anti-alpha-enolase autoantibodies in pathogenicity of
autoimmune-mediated retinopathy. J Clin Immunol.
described in tumors of the breast, ovary, and 2007;27(2):181–92.
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not appear to cause the damage. Rather, “killer mune retinopathy. J Autoimmun. 2009;32(2):133–9.
13.
Dhingra A, Fina ME, Neinstein A, et al.
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the most likely mediator of neuronal injury [109]. nopathy target TRPM1 cation channels of retinal
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the underlying malignancy, corticosteroids, and attenuate the electroretinogram in mice. PLoS One.
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Index
A symptoms, 40
Ablative therapy, 7, 13 treatment, 43–45
Acquired astrocytoma, 46, 47 ultrasonography, 42
Acquired immune deficiency syndrome (AIDS), 84 Ataxia telangiectasia (AT), 115
Acquired tumors of ciliary epithelium cerebellar ataxia, 136
adenoma and adenocarcinoma clinical features, 136
clinical features, 77–79 diagnosis, 137
management, 80 dysplasia of the thymus gland, 136
pathology, 77, 80 endocrine abnormalities, 137
pseudoadenomatous hyperplasia genetic aspects, 136
age-related hyperplasia, 75–77 pathogenesis, 136
reactive hyperplasia, 75, 76 progeric changes, 137
Adenocarcinoma prognosis, 137
diagnostic evaluation, 62–64 recurrent pulmonary infections, 136
etiology, 61 susceptibility to neoplasia, 136
pathology, 61, 62 telangiectasias, 136
signs, 62, 63 treatment, 137
symptoms, 62 Ataxia telangiectasia-like syndrome
treatment, 64 (ATLD), 137
Adenoma Autosomal recessive microcephaly, 60
diagnostic evaluation, 64
etiology, 61
pathology, 61, 62 B
prognosis, 65 Bear tracks, 54, 55
signs, 62, 63 Bilateral diffuse uveal melanocytic proliferation
symptoms, 62 (BDUMP)
Adult Coats’ disease, 33 cultured melanocyte elongation and proliferation
Age-related hyperplasia, 75–77 factor, 157
Anti-VEGF therapy, 12 diagnostic evaluation, 157
in Coats’ disease, 13 differential diagnosis, 159
intravitreal injections, 33, 34 histopathology, 156
retinal capillary hemangiomas, 26 prognosis, 159
vasoproliferative tumors, 33, 34 signs, 157
Astrocytic hamartoma, 3 symptoms, 157, 158
association with tuberous sclerosis, 46 treatment, 159
diagnostic evaluation, 40 Blood-brain barrier (BBBD), 96
differential diagnosis, 42, 43 B lymphocytes, 84, 90
fluorescein angiography, 41 Bonnet-Dechaume-Blanc syndrome, 131
fundus autofluorescence imaging, 41 Bourneville’s disease, 39
pathogenesis, 39
pathology, 39
prognosis, 46 C
signs, 40, 41 Café-au-Lait Macules, 117, 118
spectral-domain OCT, 42 Calcified type 2 tumors, 41

https://doi.org/10.1007/978-3-030-04113-7
166 Index
Cancer associated retinopathy (CAR) Coats’ plus disease, 9

diagnostic evaluation, 149, 151 Coats’-like retinitis pigmentosa, 9
differential diagnosis, 151–152 Combined hamartoma of the retina and retinal pigment
etiology, 148 epithelium (CHR)
photoreceptor degeneration, 148 associated systemic disorders, 65
prognosis, 152 diagnostic evaluation, 65, 66
signs, 149 etiology, 65
symptoms, 149, 150 pathogenesis, 65
treatment, 152 pathology, 65
Cavernous angiomas, 139, 140 prognosis, 67
Central nervous system (CNS) hemangioma, 123, 124 signs, 65, 66
Central neurofibromatosis, see Neurofibromatosis symptoms, 65
type 2 treatment, 66, 67
Cerebellar ataxia, 136 Congenital grouped pigmentation
Cerebral cavernous malformation syndromes, 132 bear tracks, 54
Cerebral cavernous malformations (CCM), 132, 133 clinical features, 56
Cerebroretinal microangiopathy with calcifications and diagnostic evaluation, 57
cysts (CRMCC), see Coats' plus disease etiology, 54, 56
Cerebrospinal fluid analysis, 160 features, 58
Choroidal tumors, 93 histopathology, 56, 57
Chronic posterior uveitis, 90 pathogenesis, 56
Ciliary epithelium prognosis, 57
acquired tumors treatment, 57
adenoma and adenocarcinoma, 77–80 Congenital hypertrophy of the retinal pigment epithelium
pseudoadenomatous hyperplasia, 75–77 (CHRPE), 3
anatomy, 71 depigmentation, 54
congenital tumors diagnostic evaluation, 53–55
glioneuroma, 71, 72 etiology, 51
medulloepithelioma, 72–75 features, 58
Zimmerman’s histological classification, 71 pathogenesis, 51
Coats’ disease, 2 pathology, 51, 53
clinical features, 6, 7 prognosis, 54
diagnostic evaluation signs, 52, 53
computerized tomography, 8, 9 solitary, 51, 52
fine needle aspiration, 9 symptoms, 52
fluorescein angiography, 7 treatment, 54
magnetic resonance imaging, 9 Congenital retinocephalofacial vascular malformation
optical coherence tomography, 7 syndrome, 131
optical coherence tomography angiography, 8 Congenital tumors
ultra-widefield images, 7, 8 glioneuroma, 72
differential diagnosis, 10–12 medulloepithelioma, 72
etiology and pathogenesis, 5, 6 association with pleuropulmonary
ophthalmic association, 9, 10 blastoma, 75
prognosis, 15 clinical features, 72–75
with syndromes, 9 management, 74, 75
systemic association, 9 pathology, 73
treatment Coronal adenoma, see Age-related hyperplasia
ablative therapy, 13 Cryotherapy, 12
anti-VEGF therapy, 12, 13 retinal capillary hemangiomas, 24
classification, 6 vasoproliferative tumors, 34
cryotherapy, 12, 13 Cultured melanocyte elongation and proliferation
dexamethasone implants, 13 (CMEP) factor, 157
follow-up, 15 Cutaneous hemangioma, 130
intravitreal corticosteroid injection, 13 Cystadenoma, 125
intravitreal triamcinolone injection, 13
laser photocoagulation, 12
observation, 12 D
supportive care, 15 Dexamethasone implants, 34
surgical drainage, 14, 15 Diffuse choroidal hemangioma, 130
vitreoretinal techniques, 15 Diffuse large B-cell lymphoma, 84, 90
Index 167
E M
Encephalofacial angiomatosis, 115 Macular fibrosis, 7
Enhanced depth Imaging OCT (EDI-OCT), 63 Maculopathy, 96, 97
Epilepsy, 128 Mammalian target of rapamycin (mTOR) pathway, 128
Epiretinal membranes (ERM), 26–27, 65, 67, 121 Mammalian target of rapamycin (mTOR)-mediated
Epithelial-to-mesenchymal transition (EMT), 101 signaling, 39
Epstein-Barr virus infection, 84 Mannitol maculopathy, 97
External beam radiotherapy (EBRT), Massive gliosis, 43
94–96, 109 Massive retinal gliosis, 3
Exudative retinal detachments, 10 Medulloepithelioma
Exudative retinitis, 5 association with pleuropulmonary blastoma, 75
Exudative retinopathy, 12 clinical features, 72–75
management, 74, 75
pathology, 73
F Melanoma associated retinopathy (MAR)
Familial cerebral cavernous malformations, 133 clinical features, 153
Familial exudative vitreoretinopathy (FEVR), 11 diagnostic evaluation, 153
Familial progressive cerebellar ataxia, 136 differential diagnosis, 153, 154
Familial syndrome, 75 etiology, 153
Fuchs’ adenoma, see Age-related hyperplasia management, 154
pathogenesis, 153
prognosis, 154
G signs, 153
Gamma knife radiosurgery (GKRS), 96, 109 symptoms, 153
Gardner syndrome, 57–60 Mesenchymal-to-epithelial transition, 108
Glaucoma, 118, 119, 129 Multiple miliary aneurysms, 5
Glioneuroma, 72 Myelinated nerve fibers, 43
H N
Hamartomas, see Astrocytic hamartoma Neurocutaneous melanosis (NCM), 137
Hematological malignancy, 3 Neurofibroma, 117
Hemorrhagic macrocysts, 7 Neurofibromatosis type 1 (NF1)
Highly active antiretroviral therapy Café-au-Lait Macules, 117
(HAART), 84 clinical features, 117
Human immunodeficiency virus (HIV), 84 diagnostic evaluation, 119
Hypoxia-inducible factors (HIFs), 122 genetic aspects, 116
glaucoma, 118, 119
Lisch nodules, 117, 118
I neurofibroma, 117
Incontinentia pigmenti, 11 ophthalmic manifestations, 117
Intracranial arteriovenous malformations, 30, 131 optic nerve gliomas, 118
Intracranial cavernous angiomas, 139, 140 other malignant tumors, 119
Intraocular medulloepithelioma, 72 pathogenesis, 117
Intraretinal macrocysts, 7 prognosis, 120
Intravascular lymphoma, 93 treatment, 119
Intravitreal corticosteroid injection, 13 Neurofibromatosis type 2 (NF2)
Intravitreal triamcinolone injection, 13 diagnosis, 120
genetic aspects, 120
K management, 122
Klippel-Trenaunay-Weber syndrome, 138 ophthalmic findings, 121
pathogenesis, 120
prevalence, 120
L prognosis, 122
Laser photocoagulation, 12, 23 vestibular Schwannoma, 120, 121
Leber’s multiple miliary aneurysms, 5 Neurological disease, 128
Leptomeningeal hemangiomatosis, 130 Neuro-oculo-cutaneous syndromes, 19, 26, 28
Limbal choristomas, 134 Nevus flammeus, 130
Lisch nodules, 117, 118 Non pigmented ciliary epithelium, 75, 77
168 Index
O P
Ocular paraneoplastic diseases Pancreatic tumors, 125
bilateral diffuse uveal melanocytic proliferation Paraneoplastic eye movement disorders, 160, 161
CMEP factor, 157 Paraneoplastic melanocytic proliferation, see Bilateral
diagnostic evaluation, 157 diffuse uveal melanocytic proliferation
differential diagnosis, 159 Paraneoplastic optic neuropathies (PON)
histopathology, 156 diagnostic evaluation, 160
prognosis, 159 differential diagnosis, 160
signs, 157 etiology, 159
symptoms, 157, 158 pathogenesis, 159
treatment, 159 prognosis, 160
cancer associated retinopathy signs, 160
diagnostic evaluation, 149 symptoms, 160
differential diagnosis, 151–152 treatment, 160
etiology, 148 Paraneoplastic retinopathies, 147, 148
pathogenesis, 149 Paraneoplastic vitelliform retinopathy
photoreceptor degeneration, 148 diagnostic evaluation, 156
prognosis, 152 etiology, 154
signs, 149 pathogenesis, 154
symptoms, 149, 150 prognosis, 156
treatment, 152 signs, 154, 155
melanoma associated retinopathy symptoms, 154
clinical features, 153 treatment, 156
diagnostic evaluation, 153 Pars plana vitrectomy (PPV), 26, 88, 109
differential diagnosis, 153, 154 Persistent hyperplastic primary vitreous (PHPV), 11
etiology, 153 Phakomatoses
management, 154 ataxia telangiectasia
pathogenesis, 153 cerebellar ataxia, 136
prognosis, 154 clinical features, 136
signs, 153 diagnosis, 137
symptoms, 153 dysplasia of the thymus gland, 136
opsoclonus, 160, 161 endocrine abnormalities, 136–137
paraneoplastic eye movement disorders, genetic aspects, 136
160, 161 pathogenesis, 136
paraneoplastic optic neuropathies progeric changes, 137
diagnostic evaluation, 160 prognosis, 137
differential diagnosis, 160 recurrent pulmonary infections, 136
etiology, 159 susceptibility to neoplasia, 136
pathogenesis, 159 treatment, 137
prognosis, 160 inheritance pattern, 116
signs, 160 intracranial cavernous angiomas, 139, 140
symptoms, 160 neurocutaneous melanosis, 137
treatment, 160 neurofibromatosis type 1
paraneoplastic vitelliform retinopathy Café-au-Lait Macules, 117
diagnostic evaluation, 156 clinical features, 117
etiology, 154 diagnostic evaluation, 119
pathogenesis, 154 genetic aspects, 116
prognosis, 156 glaucoma, 118, 119
signs, 154–156 Lisch nodules, 117, 118
symptoms, 154 neurofibroma, 117
treatment, 156 ophthalmic manifestations, 117
Ocular syphilis, 90 optic nerve gliomas, 118
ON bipolar cells, 148, 153 other malignant tumors, 119
Opsoclonus, 160, 161 pathogenesis, 117
Optic disc astrocytic hamartoma, 43 prognosis, 120
Optic disc drusen, 43 treatment, 119
Optic nerve gliomas, 118 neurofibromatosis type 2
Orbitofacial neurofibromatosis (OFNF), diagnosis, 120
118, 119 diagnostic evaluation, 122
Osteomas, 60 genetic aspects, 120
Index 169
management, 122 genetic aspects, 122

ophthalmic findings, 121 pancreatic tumors, 125
pathogenesis, 120 pathogenesis, 122
prevalence, 120 pheochromocytomas, 124, 125
prognosis, 122 prognosis, 125
vestibular Schwannoma, 120, 121 renal cell carcinoma, 123, 125
phakomatosis pigmentovascularis, 138, 139 retinal capillary hemangiomas, 123
retinal cavernous hemangioma treatment, 125
blood-filled saccular spaces, 133 Wyburn-Mason syndrome
CCM, 133 clinical findings, 131
clinical features, 132, 133 diagnosis, 132
fluorescein angiographic findings, 133 genetic aspects, 131
genetic aspects, 132 intracranial arteriovenous malformations, 131
ophthalmoscopic features, 133 pathogenesis, 131
pathogenesis, 132 prognosis, 132
prognosis, 133 retinal arteriovenous malformation, 131
sporadic and syndromic forms, 132 treatment, 132
treatment, 28, 133 Phakomatosis pigmentovascularis [PPV], 138
sebaceous nevus syndrome Pheochromocytomas, 125
cardiovascular defects, 134 Photodynamic therapy (PDT)
clinical features, 134 retinal capillary hemangiomas, 24, 25
cutaneous lesions, 134 vasoproliferative tumors, 34
diagnosis, 134 Photoreceptor degeneration, 148
genetic aspects, 134 Photothrombotic therapy, 34
genitourinary defects, 134 Pigment granules, 51, 56, 57
neurological manifestations, 134 Pigmented ocular fundus lesions (POFLs)
ophthalmic features, 134, 135 vs. CHRPE, 57, 58
pathogenesis, 134 diagnostic evaluation, 60
skeletal abnormalities, 134 familial adenomatous polyposis, 60
treatment, 135 features, 58
Sturge-Weber syndrome microcephaly, 60
clinical features, 129 pathogenesis, 58
diagnostic evaluation, 130 pathology, 58, 59
differential diagnoses, 129 prognosis, 60
diffuse choroidal hemangioma, 130 signs, 58–60
genetic aspects, 129 symptoms, 58
glaucoma, 129 treatment, 60
leptomeningeal hemangiomatosis, 130 Turcot syndrome, 60
nevus flammeus, 130 Plaque brachytherapy, 34
pathogenesis, 129 Pleuropulmonary blastoma (PPB), 75
prognosis, 131 Primary central nervous system lymphoma
treatment, 130 (PCNSL)
tuberous sclerosis complex central nervous system
brain and neurological manifestations, 128 clinical features, 85
clinical features, 126 diagnosis, 90
cutaneous manifestations, 128 symptoms, 84
diagnosis, 126, 128 treatment, 96–98
genetic diseases, 126 differential diagnosis, 90, 93
pathogenesis, 126 incidence, 84
prognosis, 128 ophthalmic
retinal astrocytic hamartoma, 127 clinical features, 84
treatment, 128 diagnosis, 88–90
visceral manifestations, 128 symptoms, 84
von Hippel-Lindau disease pathogenesis, 83, 84
clinical features, 122–124 prognosis, 98
CNS hemangiomas, 123, 124 Primary intraocular lymphoma, 3
cystadenoma, 125 Pseudoadenomatous hyperplasia
diagnosis, 123 age-related hyperplasia, 75
diagnostic evaluation, 125 reactive hyperplasia, 76
170 Index
R clinical features, 108, 110

Radiotherapy, 24–26 diagnosis, 108–110
Reactive hyperplasia, 76 differential diagnosis, 109
Renal cell carcinoma, 123 clinical findings, 101–108
Retinal arterial macroaneurysms, 11 pathophysiology, 101, 108
Retinal arteriovenous malformation, 29, 131, 132 prognosis, 111
Retinal astrocytic hamartoma, see Astrocytic hamartoma treatment, 109
Retinal astrocytic tumors, 3 Retinal pigment epithelial hamartoma, 3
acquired astrocytoma, 46, 47 Retinal pigment epithelium (RPE), 2, 3
astrocytic hamartoma adenoma vs. adenocarcinoma, 61–65
association with tuberous sclerosis, 46 CHR, 65–67
diagnostic evaluation, 40 CHRPE, 51–54, 58
differential diagnosis, 42, 43 classification, 52
fluorescein angiography, 41 congenital grouped pigmentation, 54, 56–58
fundus autofluorescence imaging, 41 pigmented ocular fundus lesions
pathogenesis, 39 vs. CHRPE, 57, 58
pathology, 39 diagnostic evaluation, 60
signs, 40, 41 familial adenomatous polyposis, 60
spectral-domain OCT, 42 features, 58
symptoms, 40 microcephaly, 60
treatment, 43–45 pathogenesis, 58
ultrasonography, 42 pathology, 58, 59
Retinal capillary hemangiomas (RCH), 2–3, 11, 43, 123 prognosis, 60
clinical features, 19 signs, 58–60
diagnostic evaluation, 20, 22 symptoms, 58
differential diagnosis, 22 treatment, 60
prognosis, 26 Turcot syndrome, 60
salient diagnostic findings, 20–22 simple hamartomas, 60, 61
signs, 20, 21 Retinal tumors, 2, 3
symptoms, 20 Retinal vascular abnormalities, 9
treatment Retinal vascular anomalies, 132
anti-VEGF therapy, 26 Retinal vascular tumors
cryotherapy, 24 cavernous hemangiomas
laser photocoagulation, 23 association with CNS hemangiomas, 28
juxtapapillary, 23 clinical features, 26
photodynamic therapy, 24, 25 diagnostic evaluation, 27
radiotherapy, 24–26 differential diagnosis, 28
vitreoretinal procedures, 26 prognosis, 28
VHL disease, 26 salient diagnostic findings, 28
Retinal cavernous hemangiomas, 115 signs, 26, 27
association with CNS hemangiomas, 28 symptoms, 26, 27
blood-filled saccular spaces, 133 treatment, 28
CCM, 133 clinical features, 19
clinical features, 26, 132 retinal capillary hemangiomas
diagnostic evaluation, 27 clinical features, 19
differential diagnosis, 28 diagnostic evaluation, 20, 22
fluorescein angiographic findings, 133 differential diagnosis, 22
genetic aspects, 132 juxtapapillary, 23
ophthalmoscopic features, 133 prognosis, 26
pathogenesis, 132 salient diagnostic findings, 20–22
prognosis, 28, 133 signs, 20, 21
salient diagnostic findings, 28 symptoms, 20
signs, 26, 27 treatment, 22
sporadic and syndromic forms, 132 VHL disease, 26
symptoms, 26, 27 retinal vasoproliferative tumors
treatment, 28, 133 clinical features, 31
Retinal hemangioma, 5 diagnostic evaluation, 31, 32
Retinal lymphoma, 92 differential diagnosis, 31
Retinal metastasis (RM) prognosis, 35
Index 171
salient diagnostic findings, 31 glaucoma, 129

signs, 31–33 leptomeningeal hemangiomatosis, 130
symptoms, 31 nevus flammeus, 130
treatment, 33–34 pathogenesis, 129
systemic associations, 19 prognosis, 131
Wyburn-Mason syndrome treatment, 130
clinical features, 28 Surgical drainage, 14
diagnostic evaluation, 29 Syphilitic uveitis, 90
differential diagnosis, 30
intracranial arteriovenous malformations, 30
prognosis, 30 T
salient diagnostic findings, 29–30 Telangiectasias, 136
signs, 29, 30 Tractional retinal detachment (TRD), 13, 26
symptoms, 29 Transient receptor potential channel protein 1
treatment, 30 (TRMP1), 147
Retinal vasculature, 8 Tuberous sclerosis complex (TSC)
Retinal vasoproliferative tumors, 14 brain and neurological manifestations, 128
anti-VEGF therapy, 33, 34 clinical features, 126
clinical features, 31, 34, cryotherapy cutaneous manifestations, 128
diagnostic evaluation, 31 diagnosis, 126, 128
differential diagnosis, 31 genetic diseases, 126
prognosis, 35 pathogenesis, 126
salient diagnostic findings, 31 prognosis, 128
signs, 31–33 retinal astrocytic hamartoma, 127
symptoms, 31 treatment, 128
treatment, 33–34 visceral manifestations, 128
Retinoblastoma, 2, 10, 11, 42 Tumor node metastasis (TNM) classification, 1
Retinocytoma, 2, 43 Tumor-expressed recoverin, 149
Retinoma, 2 Turcot syndrome, 60
Retinopathy of prematurity (ROP), 11 Typical retinal arteriovenous malformation, 29
RPE hamartomas associated with familial adenomatous
polyposis, see Pigmented ocular fundus
lesions U
Uveal melanoma, 47, 77, 129, 138
S
Schimmelpenning-Feuerstein-Mims syndrome, see V
Sebaceous nevus syndrome Vascular endothelial growth factor (VEGF), 5, 122, 149
Sebaceous nevus syndrome Vascular lesions, 2
cardiovascular defects, 134 Vascularized fibrosis, 8
clinical features, 134 Vestibular schwannoma (VS), 120, 122
cutaneous lesions, 134 Visceral hamartomas, 126
diagnosis, 134 Vitreo-retinal lymphoma (VRL), 3, 84, 87, 88, 90, 92, 93
genetic aspects, 134 local treatment, 93–95
genitourinary defects, 134 systemic chemotherapy, 95–96
neurological manifestations, 134 Vitreoretinal techniques, 15
ophthalmic features, 134, 135 Vitreoretinal traction, 6, 11
pathogenesis, 134 Vitreous amyloidosis, 92
prognosis, 135 Von Hippel-Lindau disease (VHL), 3, 26
skeletal abnormalities, 134 clinical features, 122–124
treatment, 135 CNS hemangiomas, 123
Simple hamartomas of RPE, 61 cystadenoma, 125
Snellen assessment, 160 diagnosis, 123
Stereotactic radiosurgery, 109 diagnostic evaluation, 125
Sturge-Weber syndrome (SWS), 115, 138 genetic aspects, 122
clinical features, 129 pancreatic tumors, 125
diagnostic evaluation, 130 pathogenesis, 122
differential diagnoses, 129 pheochromocytomas, 125
diffuse choroidal hemangioma, 130 prognosis, 125
genetic aspects, 129 renal cell carcinoma, 123
172 Index
Von Hippel-Lindau disease (VHL) (cont.) pathogenesis, 131

retinal capillary hemangiomas, 123 prognosis, 132
treatment, 125 retinal arteriovenous malformation, 131
von Recklinghausen disease, see Neurofibromatosis treatment, 132
type 1 retinal vascular tumors
clinical features, 28
W differential diagnosis, 30
Whipple’s disease, 90, 91 intracranial arteriovenous
Whole brain radiotherapy (WBRT), 96, 97 malformations, 30
Wyburn-Mason syndrome, 115 prognosis, 30
phakomatoses salient diagnostic findings, 29–30
clinical findings, 131 signs, 29, 30
diagnosis, 132 symptoms, 29
genetic aspects, 131 treatment, 30
intracranial arteriovenous malformations, 131

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Clinical Ophthalmic

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© Springer Nature Switzerland AG 2019

Cleveland, OH, USA Arun D. Singh

To my parents who educated me beyond their means, my wife Annapurna,

1 Classification of Retinal and Retinal Pigment Epithelium

Arun D. Singh, MD Department of Ophthalmic Oncology, Cole Eye

Thomas M. Aaberg Jr, MD Department of Ophthalmology, Retina

Ilya Leskov, MD Department of Ophthalmic Oncology, Cole Eye Institute,

Introduction prognostication. Yet classification can be confus-

© Springer Nature Switzerland AG 2019 1

Introduction Etiology and Pathogenesis

© Springer Nature Switzerland AG 2019 5

Clinical Features there are reports of cases presenting within the

Fig. 2.4 Diagnostic ultrasonography of the eye in

Differential Diagnosis presents at an earlier age and is more often

Table 2.2 Coats’ disease and retinoblastoma

Table 2.3 Differential diagnosis of exudative retinopathy

formed in cases of absent or minimal exudative

Cases with a shallow exudative retinal detach-

or panretinal laser photocoagulation) has Intravitreal corticosteroid injection may play a

A definitive therapy for Coats’ disease will

S. M. Salvi (*) · P. A. Rundle · I. Rennie Clinical Features

© Springer Nature Switzerland AG 2019 19

Table 3.1 Diagnostic features of various retinal vascular tumors

Symptoms p­lanning. OCT evaluation of these lesions

Diagnostic Evaluation • Single or multiple, circumscribed,

Differential Diagnosis examination reveals that the macroaneurysm is

Observation Laser Photocoagulation

tumor or to the feeder artery, or a combination of Photodynamic Therapy

an option in cases that do not respond to the usual Cavernous Hemangioma

 ssociation with Von Hippel-Lindau

Symptoms Fluorescein angiography is the most helpful

Differential Diagnosis Prognosis

The retinal vascular malformations are usually

is symptomatic or associated with a significant Intravitreal Anti-VEGF Therapy

Prognosis capillary hemangioblastoma. Indian J Ophthalmol.

Introduction where no lesion was earlier present (Fig. 4.1).

© Springer Nature Switzerland AG 2019 39

p­ ossible Mülller cell origin [11]. Blood vessels

Fluorescein angiography of retinal astrocytic background physiologic autofluorescence. Smaller

Table 4.1 Differential diagnosis of astrocytic hamartoma

Association with Tuberous Sclerosis  ox 4.2 Clinical Features of Retinal

Most astrocytic hamartomas remain stable and do

References 18. Zimmer-Galler IE, Robertson DM. Long-term obser-

Tumors of the retinal pigment epithelium  ongenital Hypertrophy of the RPE

© Springer Nature Switzerland AG 2019 51

Table 5.1 Classification of RPE lesions

studied in newborns, documenting the congeni-

instance in which neovascularization develops at

CHRPE is a benign lesion that does not enlarge

Multiple areas of circumscribed and flat retinal

Treatment Meyer et al. have suggested that the growth pat-

Table 5.2 Histopathologic findings in variants of CHRPE

The lesions are hypofluorescent on fluorescein

Grouped pigmentation can be just observed as

Prognosis is excellent. Although congenital

 igmented Ocular Fundus Lesions

Introduction Fig. 5.5 Pigmented CHRPE. Fundus appearance (a).

Cleveland, OH, USA Arun D. Singh

1 Classification of Retinal and Retinal Pigment Epithelium

Introduction prognostication. Yet classification can be confus-

Introduction Etiology and Pathogenesis

Clinical Features there are reports of cases presenting within the

Differential Diagnosis presents at an earlier age and is more often

S. M. Salvi (*) · P. A. Rundle · I. Rennie Clinical Features

Symptoms planning. OCT evaluation of these lesions

Diagnostic Evaluation • Single or multiple, circumscribed,

Differential Diagnosis examination reveals that the macroaneurysm is

Observation Laser Photocoagulation

tumor or to the feeder artery, or a combination of Photodynamic Therapy

an option in cases that do not respond to the usual Cavernous Hemangioma

ssociation with Von Hippel-Lindau

Symptoms Fluorescein angiography is the most helpful

Differential Diagnosis Prognosis

is symptomatic or associated with a significant Intravitreal Anti-VEGF Therapy

Prognosis capillary hemangioblastoma. Indian J Ophthalmol.

Introduction where no lesion was earlier present (Fig. 4.1).

p ossible Mülller cell origin [11]. Blood vessels

Association with Tuberous Sclerosis ox 4.2 Clinical Features of Retinal

Tumors of the retinal pigment epithelium ongenital Hypertrophy of the RPE

Treatment Meyer et al. have suggested that the growth pat-

igmented Ocular Fundus Lesions

Introduction Fig. 5.5 Pigmented CHRPE. Fundus appearance (a).

Clinical Features Adenoma and Adenocarcinoma

configuration with a vascularized connective tis- Clinical Features

referred with a suspected diagnosis of choroi- Treatment

Introduction inner layer, adjacent to the vitreous cavity, is the

14–16]. Other findings include a cyclitic neoplas- Pathology

Acquired Tumors of the Ciliary

tissue, and blood vessels. Clinically it is charac- Adenoma and Adenocarcinoma

Introduction forms of ocular lymphoma that affect the

17 centers based upon physician preference. Central Nervous System

in a French study, and the overall response rate Summary

Introduction mary malignancies which develop RM are cuta-

neurofibromatosis type 1 (von Recklinghausen Genetic Aspects

In one study, glaucoma was found to be more Treatment

Prognosis Genetic Aspects

ox 9.2 Characteristic Ocular

Other Cancers Treatment

Tuberous Sclerosis Complex ungual fibromas, hypomelanotic macules, and

rain and Neurological Manifestations

iffuse Choroidal Hemangioma

Prognosis Table 9.11 Clinical features of Wyburn-Mason

etinal Arteriovenous Malformation

Retinal Cavernous Hemangioma

The retinal vascular anomalies may sometime Clinical Features

etinal Cavernous Hemangioma

erebral Cavernous Malformation

Diagnostic Evaluation resorbs spontaneously without need for vitrec-

Sebaceous nevus syndrome is a sporadic disease. Ophthalmic Features

In addition to prominent cutaneous involvement, Neurological Features

Phakomatosis Pigmentovascularis (3) phacomatosis cesiomarmorata (blue spot

I ntracranial Cavernous Angiomas debate regarding the treatment modality of