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T H E U V E I T I S SYNDROM,ES:

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1111-
--11 MASQUERADE SYNDROMES:

MALIGNANCIES

Nadia Khalida Waheed and C. Stephen Foster

Nadia Khalida Waheed and C. Stephen Foster

INTRAOCULAR-CENTRAL NERVOUS s)'l1drome

syndrome (AIDS)20
( AI D S ) º and
and immune
immune suppression
suppression following
2
following

SYSTEM LYMPHOMA
SYSTEM LYMPHOMA transplant
transplant surgery,21
surgery, and
and with
with congenital
congenital immunodefi-
21
immunodefi­

ciencies
ciencies (e.g.,
( e . g . , Wiskott-Aldrich
Wiskott-Aldrich syndrome
syndrome and
and severe
severe com-
com­

Definition
Definition bined
bined immunodeficiency).
immunodeficiency).

Intraocular-central
Intraocular-central nervous
nervous system
system (CNS)
(CNS) lymphoma
lymphoma is is aa

rare
rare and
and lethal
lethal malignancy,
malignancy, most most commonly
commonly a a diffuse,
diffuse,
Clinical
C l i n ic a l Characteristics
Characteristics
large
large cell
cell l)'lnphoma
lymphoma of of B B cells,
cells, although,
although, rarely,
rarely, it
it may
may
Intraocular-CNS
Intraocular-CNS lYITIphoma lymphoma arises arises from from the the eyeeye or or thethe
also
also be
be of
of T-cell
T-cell origin.
1 Several types
origin. Several
1
types ofof lymphomas
lymphomas can can
brain,
brain, the the spinal
spinal cord,
cord, or or the the leptomeninges,
leptomeninges, and and then then
involve
involve the
the eyes.
eyes. These
These include
in.elude systemic
systemic non-Hodgkin's
non-Hodgkin's
spreads
spreads throughout
throughout the the CNS.13,
CNS. 22, 23 Systemic
13,
Systemic spread
22, 23
spread out- out­
lymphoma
lymphoma or or systemic
systemic Hodgkin's
Hodgkin's disease,
disease, bothboth of
of which
which
side
side the the CNSCNS and and eyeeye isis rare,
rare, occurring
occurring in in only about 10%
only about 10%
can
can metastasize
metastasize to to the
the eye.
eye. However,
However, intraocular
intraocular Hodg-
Hodg­
of
of autopsied
autopsied cases.
24
cases. , 25 Ocular Ocular manifestations
24• 25
manifestations antedate antedate
kin's
kins disease
disease isis exceptionally
exceptionally rare,rare, with
with only
only a a handful
handful of of
clinically
clinically evidentevident CNS CNS involvement
involvement in in 50%
5 0 % to to 80%
8 0 % of of the
the
reported
reported cases,
cases, and
and histologic
histologic documentation
documentation in in less
less than
than
cases
cases reported
reported in in the
the ophthalmic
ophthalmic literature,17,
literature, 26 although
17• 26
although
five
five eyes.
2 6 The
eyes. -
2-5
The mostmost import~nt
import�nt of of the
the lymphomas
lymphomas is is
this
this may may represent
represent an an overestimation
overestimation because because of of a a selec-
selec­
non-Hodgkin's
non-Hodgkiri's lYITIphoma
lymphoma of of the
the eye
eye and and the
the CNS
CNS (or (or
tion
tion bias bias for for patients
patients with with ocular
ocular involvement.
involvement. Overall, Overall,
intraocular-CNS)
intraocular-CNS) lymphoma,
lymphoma, also also called
c a ll e d primary
primary CNS CNS
around 20%
around 2 0 % of of patients
patients with with primary
primary CNS CNS lymphoma
lymphoma
lYITIphoma,
lymphoma, with with more than 150
more than 1 5 0 cases
cases reported. 23
reported.
exhibit
exhibit ocular ocular involvement
involvement at at the
the timetime of of diagnosis.
diagnosis.
23

Most
Most of of the
the symptoms
symptoms of of intraocular-CNS
intraocular-CNS lymphoma lymphoma
History
History are
are related
related to to the
the posterior
posterior segment-blurred
segment-blurred vision vision and/ a n d / ..
Intraocular-CNS
Intraocular-CNS lYITIphoma,
lymphoma, previously
previously termed
termed reticulum
reticulum or
or floaters
floaters are are thethe commonest.24,
commonest. 27 In
In the
24•
the early
27
early stages
stages of of
cell
cell sarcoma
sarcoma or or microgliomatosis,
microgliomatosis, waswas first
first described
described byby the
the disease,
disease, floaters
floaters may may actually
actually be be the
the only
only symptom,
symptom,
Givner in 1955.
Givner in
7 In the
1 9 5 5 . In
7
the earlier
earlier series,
series, definitive
definitive diagnosis
diagnosis without
without even even a a decrease
decrease in in visual
visual acuity.
acuity. Anterior
Anterior segmentsegment
of
of intraocular-CNS
intraocular-CNS lymphoma
lymphoma was was based
based on on histopatho-
histopatho­ sYITIptoms
symptoms such such as as redness
redness and and painpain are are very
very rare.
rare. The The
logic
logic examination
examination of of enucleated
enucleated eyes, eyes, or
or brain
brain biopsy
biopsy and
and initial
initial presentation
presentation may may be be unilateral,
unilateral, althoughalthough ultimateultimate
studies
studies at at autopsy.8
autopsy. In 1975,
In 8
1 9 7 5 , Klingele
Klingele andand Hogan
Hogan pub-
pub­ bilateral
bilateral involvement
involvement is is the
the rule.
23
rule.":, 28, 29
28• 29

lished
lished the the first
first report
report of of the
the useuse of
of aa vitreous
vitreous biopsy
biopsy Examination
Examination reveals reveals no no or or very
very mild mild external
external signs signs of of
specimen
s p e c i m e n for
for the
the diagnosis
d i a g n o s i s of
of intraocular-CNS
intraocular-CNS lym- lym­ inflammation.
inflammation. On On slit-lamp
slit-lamp examination,
examination, there there is is often
often
phoma.
phoma.? This
9 This has
has since
since become
become a a widely
widely performed
performed pro-
pro­ mild
mild anterior
anterior segmentsegment inflammation,
inflammation, with with aqueous
aqueous cells cells
cedure
cedure for for the
the diagnosis
diagnosis of of this
this condition.
7
condition.", 8,10,11
10, 11
8,
and
and flarefiare and and keratoprecipitates
keratoprecipitates on on thethe corneal
corneal endothe-
endothe­

lium.
li um
13 , 16, 21, 22, 30 The
.13'
16, 2
1. The vitreous
22• 30
v i t r e o u s typically
typically contains
c o n t a i n s large
large

Epidemiology
Epidemiology clumps
clumps or or sheets
sheets of of cells,
cells, andand a a fundus
fundus examination
examination shows shows

Although
Although it it is
is a
a rare
rare malignancy,
malignancy, the the incidence
incidence of of intra-
intra­ multifocal,
multifocal, large, yellow, sub-retinal
large, yellow, sub-retinal pigment pigment epithelium
epithelium

ocular-CNS
ocular-CNS lymphoma
lymphoma has has trebled
trebled overover thethe last
last decade,
decade, (RPE)
(RPE) infiltrates
infiltrates with with overlying
overlying solid solid pigment
pigment epithelium
epithelium

an
an increase
increase notnot correlated
correlated with
with a a correspondingly
correspondingly large large detachment 8
detachment , 17, 24, 25, 31 visualized
8• 17· 24•
visualized through
25· 31
through a a hazy
hazy vitreous
vitreous

increase
increase inin known
known predisposing
predisposing factors.
factors.
12 12
(Fig. 48-1A
(Fig. 48-lA to to D).
D ) . Ocular
Ocular findingsfindings may may be be in in excess
excess

This
This malignancy
malignancy most most commonly
commonly occurs occurs in in middle
middle to to of
of those
those expected
expected from from clinical
clinical visionvision testing.
testing. Reported
Reported

late
late adulthood,
adulthood, withwith aa median
median age age of of 50
50 toto 60
60 years
12
years":, 13;
13;
atypical
atypical presentations
presentations include include hemorrhagic
hemorrhagic retinal retinal vascu-
vascu­

however,
however, cases
cases have
have been
been reported
reported in in children,14,
children, 15 and
and
14, 15
litis
l i ti s resembling
resembling a a viral
viral retinitis,28,
r e ti n i ti s , 32 and
and a
28'
a normal-ap-
32
normal-ap­

the
the youngest
youngest reported
reported patient was 15
patient was 1 5 years
years 01d.
old.
16 16
pearing
pearing fundus fundus with with subretinal
subretinal lesions lesions noted noted only only by by flu-
flu­

The
The sex
sex distribution
distribution is is not
not clear.
clear. Although
Although an an earlier
earlier orescein
orescein angiography.
angiography. Vitreous Vitreous opacification
opacification may may make make

study
study reported
reported no no sexual
sexual predilection,
predilection, some sorne recent
recent stud-
stud­ the
the retina
retina difficult
difficult to to visualize.
visualize.

ies report
ies report a a higher
higher incidence
inciden ce inin women,11,
women, 17-19 and
11 ,
and one
17-19
one Because
Because intraocular-CNS
intraocular-CNS lymphoma lymphoma is is more
more likely likely to to

reports
reports a a higher
higher incidence
incidence inin men.
men.
12 12
involve
involve the the deep
deep brain
brain structures
structures than than the the cerebral
cerebral cor- cor­

Immune
Immune suppression
suppression seems
seems to to be
be a a risk
risk factor
factor inin the
the tex,
tex, seizures
seizures and and motor
motor s)'lnptoms,
symptoms, although although they they do do oc-oc­

development
development of of intraocular-CNS
intraocular-CNS lymphoma.
lymphoma. This This condi-
condi­ cur, are
cur, are less
less common
common than than in in patients
patients with with other
other kindskinds of of

tion
tion has
has been
been associated
associated with
with acquired
acquired immunodeficiency
immunodeficiency brain tumors. It
brain tumors. It has
has been
been reported
reported that that since
sin.ce the
the frontal
frontal

miD
miD CHAPTER
C H A P T E R 48:
48: MASQUERADE
M A S Q U E RA D E SYNDROMES:
S Y N D R O M E S : MALIGNANCIES
M A LI G N A N C I E S

~
'}'

FIGURE
F I G U R E 48-1. A to
48-1. A D, Intraocular-CNS
to D, Intraocular-CNS lymphoma. Note the
lymphoma. Note the dense
dense vitritis (A), and
vitritis (A), and the
the presence
presence of
of retinal
retinal infiltrates
infiltrates that
that should
should raise
raise the
the suspicion
suspicion

of
of intraocular-CNS
intraocular-CNS lymphoma.
lymphoma. (See
(See color
color insert.)
insert.)

lobe
lobe is is the
the most
most commonly
commonly involved
involved region
region of of the. brain,
the brain, presents usually unilaterally as anterior uveitis, iris hetero-
presents usually unilaterally as anterior uveitis, iris hetero­

changes
changes in personality and
in personality and thethe level
level ofof alertness
alertness are are com-
com­ chromia, vitritis, and
chromia, vitritis, and choroidal
choroidal infiltrates,35,
infiltrates, 36 and
35•
and it
36
it is
is

mOl)
mon at at the
the time
time of presentation. 27 CNS
of presentation.
27
CNS findings
findings suchsuch asas often
often considered
considered a a low-grade
low-grade lymphoid
lymphoid neoplasm;
neoplasm; it usu-
it usu­

headaches,
headaches, confusion,
confusion, sensory
sensory deficits,
deficits, focal
focal weakness,
weakness, ally responds to
ally responds to treatment
treatment with with corticosteroids,
corticosteroids, although
although

diplopia,
diplopía, right-left
right-left confusion,
confusion, poor poor memory,
memory, imbalance,
imbalance, sometimes
sometimes moderate
moderate doses doses of of radiotherapy
radiotherapy areare needed;
needed;

motor
motor weakness,
weakness, and and difficulty
difficulty with with gait
gait have
have beenbeen re-re­ it has aa favorable
it has favorable long-term prognosis. 36, 37
long-term prognosis.
36• 37

ported. 19 ,33 A
ported.":
33
A history
history ofof seizures
seizures in in a patient with
a patient with no prior
no prior Hoang-Xuan
Hoang-Xuan and and associates have recently
associates have recently described
described a a

history
history of of seizure
seizure disorder
disorder is is also
also a a strong
strong indication
indication of of "new" masquerade syndrome
"new" masquerade syndrome in in a patient presenting
a patient presenting with with
CNS
CNS involvement.
involvement. Thus, Thus, careful
careful CNS CNS history
history taking
taking andand histology-proven anterior
histology-proven anterior and posterior scleritis
and posterior scleritis and
and cho-
cho­

aa thorough
thorough neurologic
neurologic examination
examination are are vitally
vitally important,
important, roidal white
roidal white dots, unresponsive to
dots, unresponsive to systemic high-dose ster-
systemic high-dose ster­

as
as they
they may
may indicate
indicate CNSCNS involvement.
involvement. oids
o i d s and
and cyclophosphamide
c y cl o p h o s p h a m i d e therapy.
therapy. This
This ppatient
a ti e n t was
was

Systemic
Systemic non-Hodgkin
non-Hodgkin lymphomalymphoma presentspresents with with obvi-
obvi­ found
found to have mucosal-associated
to have mucosal-associated lymphoidlymphoid tissue
tissue lym-lym­

ous
ous systemic
systemic symptoms
symptoms (fever,
(fever, weight
weight loss,
loss, lymphadenopa-
lymphadenopa­ phoma on
phoma on aa repeat
repeat conjunctival
conjunctival biopsy.38
biopsy.
38

thy) before ocular

thy) before ocular involvement.
involvement. VVhen When ocular
ocular involvement
involvement

does
<loes occur,
occur, hypopyon
hypopyon in in anan uninflamed
uninflamed eye,29
29
eye, hyphema,
hyphema, Pathology,
Pathology, Immunology,
lmmunology, and
and Pathogenesis
Pathogenesis
and
and choroidal
choroidal infiltrates
infiltrates have
have beenbeen reported.
reported.
34 This
34
This isis Most
Most intraocular-CNS
intraocular-CNS lymphomas
lymphomas are are diffuse,
diffuse, large
large cell
cell

in
in contrast
contrast to to intraocular-CNS
intraocular-CNS lymphoma,lymphoma, which which usually
usually lymphomas
lymphomas of of B-cell
B-cell origin,39
origin, with
with a
39
a few
few reported
reported cases
cases of
of

presents
presents as as subretinal
subretinal infiltrates
infiltrates and and thus
thus may
may be be con-
con­ T-cell
T-cell origin.
origin.
1 Gross
Cross specimens
1
specimens showshow large large graygray patches
patches

fused
fused withwith melanoma
melanoma of of the
the choroid.
choroid. Similarly,
Similarly, Hodgkin's
Hodgkin's of
of subretinal
subretinal and
and retinal
retinal infiltration
infiltration aboveabove a a thickened
thickened

disease
disease almost
almost invariably presents with
invariably presents with systemic
systemic symptoms
symptoms choroid.
choroid. Collections
Collections of of lymphoma
lymphoma cells cells are are found
found be- be­

before the
before the eye
eye is
is involved.
involved. Bilateral
Bilateral anterior
anterior andand posterior
posterior tween
tween Bruch's
Bruch's membrane
membrane and and the
the RPE, RPE, with with reactive
reactive
l1
uveitis
uveitis withwith nono retinal
retinal change
change!':; uveitis
uveitis with peripheral
with peripheral (mainly T)
(mainly T) lymphocytes
lymphocytes in in the
the retina
retina and and choroid,
choroid, sur-
sur­

white,
white, flatflat retinal
retinal deposits
deposits resembling
resembling miliarymiliary tuberculo-
tubérculo­ rounding
rounding thethe BB cells.
cells.

sis 9 and anterior

sis";; and anterior uveitis
uveitis alone
1o have been
alone '? have been reported
reported in in Cytopathology
Cytopathology specimens
specimens obtained
obtained from from the the vitreous
vitreous

patients with
patients with ocular
ocular involvement
involvement in in Hodgkin's
Hodgkin's disease.
disease. of
of patients
patients with
with intraocular
intraocular lymphoma
lymphoma show show mainly
mainly reac-
reac­

Lymphoid hyperplasia of
Lymphoid hyperplasia of the uvea is
the uvea is another
another disorder
disorder tive
tive TT cells, histiocytes, necrotic
cells, histiocytes, necrotic debris,
debris, and and fibrinous
fibrinous

that
that must
must be be distinguished
distinguished from from intraocular-CNS
intraocular-CNS lym- lym­ material,
material, and
and few
few frankly
frankly neoplastic
neoplastic (B) (B) cells.cells. The
The malig-
malig­

phoma. This
phoma. This disorder
disorder isis characterized
characterized by by aa well-differenti­
well-differenti- nant
nant lymphoma
lymphoma cellscells are
are anaplastic
anaplastic (i.e.,
( i . e . , they
they have
have a a high
high

ated,
ated, small
small lymphocytic
lymphocytic infiltration
infiltration of the uveal
of the tract. It
uveal tract. It nuclear-to-cytoplasmic
nuclear-to-cytoplasmic ratio),
ratio), and
and they
they have have lobulated
lobulated nu- nu-
 CHAPTER 48:
C H A P T E R 48: .·.M~..;lI""-f~Um;;;n.A'"'.IY'm;;;
M SYNDROMES: MALIGNANCIES
A S Q U E RA D E S Y N D R O M E S : M A U G N A N C I E S E!D

clei
clei withwith multiple
multiple small nucleoli, coarse
small nucleoli, coarse chromatin,
chromatin, and and Any
An recent-onset
y recent - onset CNS CNS ssYJ-nptoms
ymptoms or or finding
findingss on on aa neu neu-­
mitotic figures
mitotic figures (see
(see Fig. Fig. 4 48-1). Immunohistochemistry
8 - 1 ) . Immunohistochemistry rologic examination
rologic examination raise raise the the suspicion
suspicio n of of CNSCNS spread.
s pr ead.

marks them
marks them positive
positive for B-cell markers
for B-cell markers (CDI0,( C D IO , CDI9,
CD19, An MRI
An MRI is is wa
warranted,
rranted, however,however, in in allall papatients
tients s suspected
uspec ted

CD20,
CD20, CD21, C D 2 1 , CD22)
C D 2 2 ) and and for monoclonal K and
for monoclonal K and A. A. chains.
chains. of ha
of having
ving CNSCNS lymphoma,
lymphoma, even even if if the
the history
history aand exalni-
nd exam i­

In
In contrast, histiocytes have
contrast, histiocytes have largelarge vesicular
vesicular or watery nu­
or watery nu- nation are
nation are negative.
negative. O On n a a co
computed
mputed tomograp tomography hy (CT (CT))
clei
clei withwith small nucleoli and
small nucleoli minimal dumping
and minimal clmnping of of the
the scan
sean or or with
with MRI, MRI, the the appearance
appearance of of anan intraocu
intraocular-CNSlar-CNS

nuclear
n u cl e a r chromatin.
c h r o m a ti n . M Macrophages have m
a c r o p h a g e s have much
uch m more
ore lymphoma is
lymphoma is characteristic,
characteristic, with with the the tum tumor or b being
eing s supra-
upra­

opaque
opaque cytoplasmcytoplasm and and somewhat
somewhat eccentric nuclei, and
eccentric nuclei, and tentorial and
tentorial and multicentric
multicentric in in 50%
5 0 % of cases. 49 U
of cases. 49
Unlike
nlike b brain
rain

they may
they may contain
c o n t a i n ingested
i n g e s t e d debris,
debris, i including
n cl u d i n g mmelanin
elanin metastasis and
metastasis and malignant
malignant gliomas, gliomas, which which show show rring ing en en-­
granules.
granules.
19
19
hancement on
hancement on administ
administration ration of of contrast,
contrast, tthese lesions
hese lesions

Cytokines
Cytokines play play an important role
an important role inin conditions
conditions involv­
involv- characteristically have
characteristically have dense dense and and di diffuse enhancement
ffuse enhancement

ing
ing immunologic
immunologic cells, cells, and intraocular-CNS lymphoma
and intraocular-CNS lymphoma is is with
wi distinct borders.
th distinct borders.
no exception.
no exception. Interleukin-4
Interleukin-4 (IL-4) (IL-4) and IL-I0 are
and IL-10 potent
are potent A lumbar
A lumbar puncture
puncture must must be be performed
performed on on allall patients
patients
growth
growth and and differentiation
differentiation factors factors for for BB lymphocytes,
lymphocytes, and and suspected
suspected of of having
having intrao intraocular-CNS
cular-CNS lymphoma,lymphoma, regard regard-­
IL-I0
IL-1 O induces
induces B B cells
cells to to secrete
secrete largelarge quantities
quantities of immu-
of immu­ less of
less of the
the results
results of of the
the neurologic
neurologic evaluation.
evaluation. Ten Ten mi millili-
llili­

noglobulin G
noglobulin G (IgG)
( I g G ) ,, IgA,
IgA, and and IgM.40
40
IgM. IL-I0 is
IL-10 is also
also a an nega-
ega­ ters of
ters of cerebrospinal
cerebrospinal fluid fluid (CSF(CSF)) is is appropriate
appropriate for for cytol
cytol-­
tive regulator
tive regulator for for IL-12-induced
IL-12-induced inflammation inflammation and and hashas ogy.
o gy. A A rrepeat lumbar p
e p e a t lumbar puncture may be
u n c t u r e may be rrequired
e q u i r e d foforr
been seen
been primarily as
seen primarily as a a cytokine-synthesis
cytokine-synthesis inhibitorY inhibitor." diagnosis. Lymphoma
diagnosis. Lymphoma cells cells are
are extremely
extremely fr fragile,
agile, and and to to
IL-6,
IL-6, a multifunctional cytokine,
a multifunctional cytokine, plays plays aa central
central role role inin optimize
optimi results, specimens
ze results, spe ci mens shouldshould be be transporte
transported d to to the
the
inflammatory
inflammatory defense mechanisms and
defense mechanisms and hashas been
been found
found laboratory immediately.
laboratory immediately. Lumbar Lumbar puncture
puncture can can b be nega-­
e nega

in
in thethe aqueous
aqueous and vitreous of
and vitreous patients with
of patients with non-neoplas­
non-neoplas- tive in
tive in aa patient
patient with with intraocular
intraocular-CNS -CNS lymphom lymphoma, since
a, since

tic uveitis.
tic uveitis. The The same same is true of
is true of IL-12
IL-12 levels, which corre-
levels, which corre­ CNS disease
CNS disease may may lag lag ocular
ocular disease
disease by by months
months to to years
yearsY .17

late
late to to the
the degree
degree of of inflammation.
inflammation.
42 42 IL-10
IL-I0 has has been
been Even
E ven inin the
the p presence
resence of of CNS
CNS involvement,
involvement, lumbar lumbar punc punc-­
reported to
reported to bebe associated
associated with with the the presence
presence of malignant
of malignant ture can
ture can give
give false
false-negative
-negative resultsresults as as aa result
result of of mishan
mishan-­
lymphoid
lymphoid neoplasms.neoplasms. 43 ,44 The
43• 44
The rolerole of of IL-I0
IL-10 levels
levels in the
in the dling of
dling of the
the specimens
specimens or or steroid
steroid therapy
therapy;; steroidssteroids may may
diagnosis
diagnosis of of intraocular-CNS
intraocular-CNS lymphoma lymphoma is is discussed
discussed in in be cytolytic
be cytolytic in in intraocular
intraocular-CNS lymphoma and
-CNS lymphoma and may may eve even n

the
the section
section on on diagnosis.
diagnosis. cause intraocular-Cl-lf
cause intraocular-CNS lymphoma lymphoma lesions lesions to to dec
decrease
r ease in in
At
At thethe genetic
genetic level, translocation of
level, translocation BCL2 gene,
the BCL2
of the gene, a a size.
si z e.

proto-oncogene located
proto-oncogene located on on chromosome
chromosome 18, 1 8 , is believed
is believed Vitreous
V biopsy of
itreous biopsy of an an eyeeye with
with moremore severe severe vi vitritis
tritis o orr
to be
to be the
the fundamental
fundamental event event ill''fmany hematologic malig­
inemany hematologic malig- reduced vision
reduced vision is is used
used to to assess
assess ocular
ocular involvement
involvement and and is is
nancies, including
nancies, including non-Hodgkinnon-Hodgkin lymphoma,45 lymphoma,
45
where aa
where carried out
carried even if
out even the lumbar
if the lumbar puncture
puncture rresults esults are are neganega-­
t(14;18) translocation brings
t ( l 4 ; 18 ) translocation brings the BCL2 gene
the BCL2 gene into juxtapo-
into juxtapo­ tive. This
tive. This isis the
the gold
gold standard
standard for for assessing
assessing ocular ocular involve
involve-­
sition
sition with with thethe Ig heavy-chain promoter
Ig heavy-chain promoter locatedlocated on on chro-
chro­ ment in
ment in the
the disease.
disease. A A standard
standard th three-port
ree-port pa pars plana
rs plana

mosome
mosome 14,46
46
14, resulting in
resulting in overexpression
overexpression of of the BCL2
the BCL2 vitrectomy
vi trectomy (PPV)
(PPV) is p
is performed;
erformed ; before before inst instituting
ituting the the
gene.
gene. Several
Severa! investigators
investigators have have also also detected
detected this this immu-
immu­ infusion, 11 ml
infusion, ml of of u undiluted vitreous is
ndiluted vitreous is obtained
obtained by by a a
noglobulin heavy-chain
noglobulin heavy-chain rrearrangement by polymerase
e a r r a n g e m e n t by polymerase syringe
s yringe and and delivered
delivered immediately
immediately to to the
the cytolo
cytology labora-
gy labo ra­

chain reaction (PCR)

chain reaction (PCR) in
in ocular
ocular specimens
specimens of patients
of patients tory.21, 26 T
tory.
21• 26
The specimens are
he specimens are fifixed
xed by by mixing
mixing one one partpart of of
with intraocular-CNS
with intraocular-CNS lymphoma. lymphoma.v-, 47, 48
44
47, 48
10% neutral-buffered
1 0 % neutral -buffered formalinformalin wi with
th oneone part part of of specimen
specimen
for approximately
for approximately 12 hours. A
1 2 hours. A 55-ml
-ml fifixed specimen is
xed specimen is the
then n

Diagnosis
Diagnosis spun at
spun at 1000
10 00 r rpm
pm for for 55 minutes
minutes in in aa cytospin
cytospin chamber chamber to to
The three cornerstones
The three cornerstones of of diagnosis
diagnosis in intraocular-CNS
in intraocular-CNS concentrate the
concentrate the cells
cells ontoonto glass
glass slides.
slides. These These are are thenthen
lymphoma
lymphoma are are a thorough CNS
a thorough CNS evaluation
evaluation (including
(including a a dried and
dried and stained
stained with with aa modified
modified P Papanicolaou's
apanicolaou ' s staining staining
history and
history neurologic examination
and neurologic examination as well as
as well magnetic
as magnetic technique
t e c h n i q u e foforr ccytopathologic
ytopathologic a analysis.
nalysis. H Histochemical
istochemical

resonance imaging
resonance imaging [MRI]),
[ M RI ] ) , CNS
CNS cytology,
cytology, andand a a diagnos-
diagnos­ staining
staining using using monoclonal
monoclonal antibodies antibodies against against the the B B-- anandd

tic
tic vi trectomy. The
vitrectomy. The differential
differential diagnoses
diagnoses of of sarcoid
sarcoid and,and, T-cell
T markers and
-cell markers and against
against K andK and A. A. li
light
ght chainschains is is als
alsoo

less
less commonly, tuberculosis, which
commonly, tuberculosis, which ma may present in
y present in aa simi-
simi­ done,, and
done and thethe slides
slides are are interpreted
interpreted by by a a cytopathologis
cytopathologist. t.

lar way,
lar wa must be
y, must be excluded
excluded with with appropriate
appropriate investigations.
investigations. .. Total
Total vivitrectomy
trectomy is is then
then performed
performed w withith in infusion.
fusion. Tis Tis-­
A high
A high indexindex of of suspicion
suspicion for for intraocular-CNS
intraocular-CNS lym- lym­ sue cult
sue culture medium enriched
ure medium enriched wi with
th 10%1 0 % fetalfetal calf
calf se serum
ru m

phoma
p homa is necessary
is necessar to avoid
y to missing or
avoid missing or delaying
delaying the the diag-
diag­ can be
can be added
added to to the
the collection
collection chamberchamber of of the
the vitrectomy
vitrectomy
nosis especially in
nosis,, especially middle-aged
in middle -aged or or older patients pre
older patients pre-­ machine to
machine to improve
improve ccell viability.
ell viabili This diluted
ty. This diluted specimen
specimen
senting
senting withwith chronic
chronic vi vitritis.
tritis.
39 Findings
Findings of
39
of intense
intense ocular
ocular is then
is then susubmitted
bmitted fo forr modified
modified Papani Papanicolaou's staining,
co laou ' s stainin g,

inflammation
inflammation (in the absence
(in the absence of of significant pain, photo
signi ficant pain, photo-­ histochemical staining,
histochemical staining, flow flow cytometry,
cytometry, and and IIL L a analysis.
nalysis.

phobia, or
phobia, or conjunctival
conjunctival h hyperemia),
yp eremia), and and sub-RPE
sub-RPE infil-
infil­ Problems
P encountered are
roblems encountered are similar
similar to to those
those o off lumbar
lumbar
trates, sheets
trates, sheets and and clumps
clumps of vitreous cells,
of vitreous ce ll s, and
and steroid
steroid puncture specimens
puncture specimens:: the the fr fragility
agility of of thethe lympho
lymphoma ma cellscells
resistance (after
resistance ( after a possible initial
a possible initial period
period of of steroid re-­
ste ro id re (which may
(which may be be damaged
damaged by by impro
improper handling), steroi
p er handling), steroid d

sponsiveness), should
sponsiveness), raise suspicion
should raise suspicion forfor intraocular-CNS
intraocular-CNS therapy (which
therapy (which most most of of these
these individuals
individuals w were
ere on on for for
lymphoma.
lymphoma. The reported average
The reported average interval
interval of of 2211 months
months vitritis prior
vitritis prior to to thethe vitrectomy),
vitrectomy), and and the the high high rratio atio o off

between
be tw een the the onset
onset of of ocular
ocular symptoms
symptoms and and definitive
definitive reactive cells
reactive cells to to malignant
malignant cells. cells. TheThe diagnosis
diagnosis ca can easily
n easily
ll
diagnosis
diagnosis!' has has been
been shown
shown to to be
be reduced
reduced considerably,
considerably, be missed
be missed b by pathologists
y patholo who have
g ists who have had had litt little experience
le exp e rience

with most patients

with most patients diagnosed
diagnosed be between
tw een 2020 andand 52 weeks,
52 weeks, with
wi this co
th this condition.
ndition. False False ne negatives
gatives can can be be minimi
minimized z ed b byy

if
if one maintains aa high
one maintains high index
index of of suspicion
suspicion based based on on immediate delivery
immediate delivery of of the
the specimens
specimens and and by by the
the availabil
availabil-­
clinical
clinical findings.
fi ndin g s.
1919
ity
i ty of of an
an experienced
experienced cytopathologis
cytopathologist. t. E Even
ven so, so, mul
multiple
tiple
l!!Ifl . CHAPTER
C H A P T E R 48:
48: MASQUERADE
M A S Q U E R A D E SYNDROMES:
S Y N D R O M E S : MALIGNANCIES
M A LI G N A N C I E S

vitreous
vitreous samples
samples may may be be needed
needed to to make
make aa definitive
definitive Prognosis
diagnosis.":,50
diagnosis. 25 50
Prognosis of
Prognosis of this
this co
condition
ndition is is poor,
poor, despite
despite aa genera
generallylly
Ancillary diagnostic
Ancillary modalities include
diagnostic modalities include thethe measure­
measure- good initial
good initial response.
response. The
The 5-5-year
year s survival is less
urvival is less than
than 55% %
ment of
ment of ILIL levels.
levels. High
High IL-10
IL-1 O levels
levels and
and anan elevated
elevated ratio ratio and median
and median sur survival varies in
vival varies in di
different series from
fferent series from 13 to
1 3 to
of
of IL-10
IL-1 O to to IL-6
IL-6 in vitreous specimens
in vitreous specimens have have been
been associ-
associ­ 26 months. 12 , 17, 25 Char
26 months.": Char and
17·
and co
26
colleagues, however, suggest
ll eagues, however, suggest
ated with intraocular-CNS
ated with intraocular-CNS lymphoma,
lymphoma, according
according to to some
sorne that the
that the median
median survival
survival in
in these
these patients
patients improves
improves if if a
a
reports. 5l ,52 However,
reports.":
52
However, aa study
study atat our
our center
center shows
shows that that IL-
IL- combination of
combination of intrathecal
intrathecal chemotherapy
chemotherapy and and radiother
radiother-­
10 can
10 can bebe detected
detected even
even in vitreous specimens
in vitreous specimens of patients
of patients apy of
apy of the
the CNS
CNS andand orbit
orbit is employed. 25
is employed. 26

with non-neoplastic
with non.:.neoplastic uveitis
uveitis and that, conversely,
and that, conversely, IL-10IL-1 O lev-
lev­

els are
els not always
are not always elevated
elevated in patients with
in patients with intraocular-
intraocular­ Complications
Complicatlons
CNS
CNS lymphoma.
lymphoma.
53 Thus
Thus IL-10
53
IL-10 levels
levels are
are suggestive
suggestive but but not
not Cranial radiotherapy produces significant CNS toxicity in
Cranial radiotherapy produces significant CNS toxicity in

diagnostic
diagnostic of of lymphoma,
lymphoma, with with vitreous
vitreous biopsy
biopsy cytopathol-
cytopathol­ long-term
long survivors,, which
-term survivors which is is exacerbated
exacerbated by by chemother
chemother-­
ogy
ogy still being the
still being the only
only definitive means of
definitive means of diagnosing
diagnosing apy,13, 50 especia
apy,
13,
especially
60
MTX. However,
lly MTX. However, administration
administration of of che
che-­
ocular
ocular involvement
involvement in in intraocular-CNS
intraocular-CNS lymphoma.
lymphoma. motherapy be
motherapy before radiotherapy may
fore radiotherapy may reduce
reduce the the ris
risk of
k of

Several
Several investigators have identified
investigators have the tt(l4;18)
identified the ( l 4 ; 1 8 ) locus
locus leukoencephalopathy
leu k oencephalopathy and and late
late toxici
toxicity.
ty. 50, 51 So
Some
60,
investi-­
61
rn e investi

by PCR
by PCR in in ocular
ocular specimens
specimens of patients with
of patients with intraocular-
intraocular­ gators
g recommend using
ators recommend using systemic
systemic and
and intrathecal
intrathecal cchemo-h emo­

CNS
CNS lYlnphoma,47,48
lymphoma, and
and successful
47• 48
successful amplification
amplification in both
in both therapy for
therapy for intraocular
intraocular-CNS-CNS l lymphoma,52
ym phoma, with radiother
with radiother-­
62

frozen
frozen and and formaldehyde-fixed
formaldehyde-fixed and paraffin-embedded
and paraffin-embedded apy u
apy used only fo
s e d only forr rrecurrent
ecurrent d disease.
isease. T This
his ttends to
e n d s to

samples
samples have have beenbeen reported
reported using
using this method. 54 ,55 Thus
this method. Thus 54· 55
minimize the
minimize the toxici
toxicity associated with
ty associated with co
combination
mbination chemo chemo-­
this promising
this promising new new method
method may may provide
provide anan additional
additional therapy and
therapy and radiotherapy
radiotherapy usage.usage. Survival
Survival ratesrates may
may im im-­
diagnostic
diagnostic clue when traditional
clue when traditional methods
methods fail
fail toto provide
provide prove wi
prove with
th a a co
combination
mbination of of intr
intrathecal chemotherapy
athecal chemotherapy

an unequivocal answer.
an unequivocal answer. and radiotherapy
and radiotherapy to to the
the orbits
orbits and
and whole brain. 25
whole brain. 26

Treatment
Treatment
Conclusion
Conclusion

Intraocular-CNS lymphoma is an insidious and aggressive

Intraocular-CNS lymphoma is an insidious and aggressive
The
The optimal treatment of
optimal treatment of intraocular-CNS
intraocular-CNS lymphoma lymphoma is is
malignancy that
malignancy that presents
presents mas
masquerading
querading as as intraocular
intraocular
still
still controversial.
c o n troversial. In In the the casecase of of documented
d o c u m e n t e d CNS CNS
inflammation.
in fl ammation. AA high
high in
index of suspicion,
dex of suspicion, aa thorough
thorough CNS
CNS
involvement,
involvement, combined combined radio- radio- and and chemotherapy
chemotherapy is is rec­
rec-
evaluation, and
evaluation, and cytologic
cytologic examination
examination ofof vitreous
vitreous sample
sampless
ommended.
ommended. Whole Whole brain brain radiation
radiation with with 50 gray (Gy)
50 gray (Gy) and and
are the
are the cornerstones
cornerstones of of diagnosis.
diagnosis. M
Management
anagement is is contro
contro-­
an
an additional
additional 10-Gy 10-Gy boostboost to to thethe tumor
tumpr side side is is recom­
recom-
versial, but
versial, but ea
earlier diagnosis aand
rl ier diagnosis new tr
nd new treatment modal-­
eatment modal
mended.18, 28 However,
mended.l"
28
However, despite despite high high radiosensitivity,
radiosensitivity, whole whole
ities pro
ities provide some
vide so hope for
rn e hope for patients
patients with
with this
this condition.
condition.
brain radiation
brain radiation alone alone leadsleads to to aa highhigh relapse
relapse rate, rate, withwith
most patients
most patients dying within 11 to
dying within to 55 years
years of diagnosis. 28 A
of diagnosis.
28
A
LEUKEMIAS
marked improvement
marked improvement in in survival
survival of patients is
of patients is reported
reported
when cranial
when radiation is
cranial radiation is combined
combined with with intrathecal
intrathecal meth­ meth- Definition
D e fi n i t i o n
otrexate
otrexate (MTX) (MTX) as as systemic
systemic chemotherapy.55
chemotherapy.
56
Intrathecal
Intrathecal
Leukemias are malignant neoplasms of the hematopoietic
Leukemias are malignant neoplasms of the hematopoietic
MTX is
MTX needed because
is needed because the the CNSCNS levelslevels of of intravenous
intravenous
stem ce
stem cells, characterized by
ll s, characterized by didiffuse replacement of
ffuse replacement of the
the
(IV)
(IV) chemotherapy may be be short-lived 57 and
57
variable, de- 53 Traditiona
chemotherapy may short-lived and variable, de­
bone marrow
bone marrow by by neoplastic
neoplastic ce cells. 63
ll s. Traditionally, leuke-
lly, leu ke­
spite
spite thethe fact that high
fact that high-dose
-dose cytosine
cytosine arabinoside
arabinoside can can lead
lead
mias are
mias are classified
classified on on thethe basis
basis of of the the cecell type
ll ty involved
pe involved
to therapeutic
to therapeutic levels levels inin CSF.32
CSF. MTX may
MTX
32
may also also be be delivered
delivered and on
and on thethe maturi
maturity ty ofof the
the leuleukemic
k emic ce cells into acute
ll s into acute
by an
by an Omaya reservoir,27 and
Omaya reservoir, and intravitreal
27
intravitreal M MTX TX has has been
been lymphocytic
lymphocy ti c ((ALL), acute myeloc
A L L ) , acute myelocytic yti c ((AML)
A M L ) ,, ch chronic
ro nic
employed
e m p l o y e d in in some
s o rn e ppatients with intraocular-CNS
a ti e n t s with intraocul a r - CNS lym- lym­ lymphocytic ((CLL)
lymphocytic C L L ) ,, and
and cchronic myelocytic (my
hronic myelocytic (myeloge-
eloge­
phoma wi
phoma with promising resu
th promising results.lts. 58
58
nous) (CML)
nous) (CML) leu leukemias.
k emias. The The acute
acute leu leukemias
k emias are are charac
charac-­
Radiation
R therapy has
adiation therapy has proved
proved to to bebe effective
effective for for ocular
ocular terized
teri z ed byby the the presence
presence of of very
very immature
immature ce cells called
ll s ca lled

findings
findings in patients with
in patients with detectable
detectable involvement
involvement only only in in blasts and
blasts and aa rrapidlyapidly fa fatal
tal cocourse
urse in in untreated
untreated patients;
patients;
the eye
the eye andand no no detectable
detectable CNS CNS involvement.
involvement. A A dose
<l ose ofof chronic leu
chronic leukemias
kemias a are associated, at
re associated, at least
least initia
initially, with
lly, with

30
3 0 Gy
Gy is is given, typically
given, typica ll y toto b both
o t h eyes,
e y e s , since bilateral
s i n c e bilateral well-differentiated
we ll-differentiated leu leukocytes,
k ocytes, andand wi with
th a a rrelatively
elatively indo indo-­
involvement
involvement is. the rule.
is the rule. 18, 25, 28 In
18·
In these
26·
these patients,
28
patients, there there is is lent cour
lent course. se. TheThe acute
acute leu leukemias
kemias typ typically exhibit
ically exhib the
it the

controversy
controversy about whether to
about whether to limit
limit tretreatment
at ment to to thethe eyeeye characteristics of
characteristics of an
an abrupt,
abrupt, ""stormy"
stormy " onset, onset, withwith sympsymp-­
or to prophylactica
or to prophylactically lly irradiate
irradiate the the CNS
CNS as as wwell. Although
ell. Al though toms related
toms related to to depression
depression of of normal
normal bone bone marrow
marrow fu func-
nc­

one
one group
group of investigators has
of investigators has reported
reported long long-term
-term ( (24
24 tion, organ
tion, organ in infiltration,
filtration, and and CNS CNS manifestations.
manifestations. T The
he al al-­
and
and 109 months) disease
1 0 9 months) disease-free -free survival
survival wit with h ocuocular radia-­
lar radia teration in
teration in normal
normal marrowmarrow fu function
nc ti on and and thethe aability
bility to to
tion only,
tion only,25 many
26
many researchers
researchers recommend recommend proph prophylactic
ylactic infiltrate
in tissues, especia
filtrate tissues, especially common
lly co mmon in in ALALL,L, isis responsi
responsi-­
CNS radiation in
CNS radiation in addition
addition to to orb
orbital radiation in
ital radiation inpatients
patients ble for
ble for many
many of of the
the ocular
ocular manifestations
manifestations.. The The chronic
chronic
with
wi th isolated
isolated ocular involvement,
ocular invol vement, since since th these
ese pa patients of-­
ti e n ts of leukemias,
leu k emias, a although
lthough a a more
more diverse
diverse group group of of disorders,
disorders,
ten have
ten have subclinical
subclinical CNS involvementt b
CNS involvemen by
y ththee titime
me o ocular
cular do, to
do, to so
some extent,, share
rn e extent share thethe same
same properties.
properties.
manifestations arise.
manifestations
25
arise. ,59 R
26·
Rouwen
59
ouwen and and c colleagues
o ll ea g ues
59 advise
59
advise Leukemic
Leu ophthalmopathy w
kemic ophthalmopathy was apparently
as apparen first
tly fir estab-­
st estab

aa combination
combination of of chemotherapy
chemotherapy for for C CNS disease and
NS disease and lished as
lished as aa clinical
clinical entientityty inin the
the late late 119th century b
9 th century byy

radiotherapy
radiotherap y for
for ocular disease even
ocular disease even if if CNS
CNS involvement
involvement Liebreich in
Liebreich in his
his paper
paper on on leu
leukemic retinopathy and
k emi c retinopathy and cen cen-­
cannot
cannot be be documented·
documented by by M MRIRI and and lum lumbar bar puncpuncture,ture, tral retinal
tral retinal artery embolism. 54 In
artery embolism. 64
In the the earl
earlyy 1 1900s, leuke-
9 0 0 s , leu ke­

since penetration of
since penetration of thethe blood
blood-brain barrier b
-brain barrier byy chchemo-
emo ­ mic invasion of the optic
mic invasion of the optic nerve
nerve was was considered
considered aa preter preter-­
therapeutic
ther apeutic agentsagents is is doub
doubtful. tful. minal curiosi
minal curiosity; however, with
ty; however, with advances in the systemic

iM
 CHAPTER
C H A P T E R 48:
48: MASQUERADE
M A S Q U E R. A D E SYNDROMES:
S Y N D R O M E S : MALIGNANCIES
MAUGNANCIES

treatments
treatments ofof leukemia,
leukemia, there
there was
was a
a resurgence
resurgence ofof interest
interest initiation
initiation of
of treatment
treatment can
can be
be life
life saving,
saving, especially
especially HI
111

in
in the
the eye
eye as
as aa site
site where
where leukemic
leukemic cells
cells may
may escape
escape acute
acute leukemias.
leukemias.

the
the effects
effects of
of systemic
systemic treatment
treatment and
and later
later proliferate
proliferate to
to

cause
cause relapse.
relapse. Retina
Retina
Leukemic
Leukemic retinopathy
retinopathy is is observed
observed in in both
both the the acute
acute and and

Epidemiology
Epidemiology chronic
chronic forms
forms of of leukemia,
leukemia, but but it
it is
is common
common in in the
the acute
acute

Estimates
Estimates of of ocular
ocular involvement
involvement in in leukemia
leukemia vary:
vary: Patho-
Patho­ form.
form. It It is
is characterized
characterized by by tortuous,
tortuous, dilated
dilated retinal
retina! veins,
veins,

logic
logic studies
studies show
show a a higher
higher incidence
incidence than than clinical
clinical ones
ones which
which may may have have an an irregular
irregular "boxcar"
"boxear" or or "sausage"
"sausage" ap- ap­

and
and many
many findings
findings are
are transient,
transient, waxing
waxing andand waning
waning with
with pearance. 74 Perivascular sheathing
pearance.?" Perivascular sheathing is is often
often present
present and and is is

time
time and
and treatment.
treatment. Ridgeway
Ridgeway and and associates,65
associates, for
for exam-
65
exam­ thought
thought to to represent
represent infiltration
infiltration of leukemic cells.
ofleukemic cells.
75 Hard
75
Hard

ple,
ple, report
report abnormalities
abnormalities on on ocular
ocular examination
examination in in 9%
9 % of
of exudates
exudates and and cotton-wool
cotton-wool spots spots are are also
also a a prominent
prominent

children
children suffering
suffering from
from acute
acute leukemias,
leukemias, whereas
whereas Duke-
Duke­ feature;
feature; the the cotton-wool
cotton-wool spots spots have
have been been suggested
suggested to to be
be

Elder 66 estimates that

Elder'" estimates that up to 90%
up to 9 0 % ofof patients
patients with
with leukemia
leukemia either
either nerve
nerve fiber
fiber layer
layer infarcts
infarcts or or localized
localized collections
collections of of

demonstrate
demonstrate some sorne ocular
ocular abnonnality
abnormality at at some
sorne point
point inin leukemic
leukemic cells.cells.
76
76

the
the disease
disease course.
course. However,
However, it it is
is generally
generally accepted
accepted thatthat The
The most
most striking
striking feature
feature of of leukelnic
leukemic involvement
involvement of of

the
the eye
eye is
is involved
involved farfar lTIore
more often
often in in acute
acute than
than in
in chronic
chronic the
the retina,
retina, however,
however, is is the
the presence
presence of of retinal
retina! hemor-
hemor­

leukemias.
leukemias. For For example,
example, Kincaid
Kincaid and and Green,67
Green, in
in a a review
67
review rhages,
rhages, most most commonly
commonly located located in in thethe posterior
posterior pole pole

of
of pathology
pathology specimens,
specimens, report
report ocular
ocular involvement
involvement in in (Fig. 48-2A,
(Fig. 48-2A, B). B ) . These
These hemorrhages
hemorrhages may may be be at at any
any level
level

82%
8 2 % of
of cases
cases of of acute
acute andand inin 75%
7 5 % ofof chronic
chronic leukemic
leukemic of
of the
the retina,
retina, including
including extension
extension into into the
the subretinal
subretinal or or

eyes,
eyes, and
and thisthis difference
difference isis noted
noted in in most
most other
other studies
studies vitreous
vitreous spaces.
spaces.
7575 Most
Most commonly
commonly they they areare intraretinal,
intraretinal,

as
as well.
well. either
either round
round or or flame
flame shaped.
shaped. These
These intraretinal
intraretinal hemor-hemor­

rhages
rhages may may appear
appear as as the
the classic
classic white-centered
white-centered Roth's Roth's

Clinical
C l i n i c a l Presentation
Presentatlon and
and Diagnosis
Diagnosis spots,
spots, with
with the the white
white centers
centers representing
representing cellularcellular debris,
debris,

As
As effective
effective chemotherapy
chemotherapy programs programs have have ledled to to longer
longer capillary
capillary emboli,
emboli, or or accumulations
accumulations of of leukemic
leukemic cells.
76
cells.":, 77
77

survival
survival times
times for for leukemic
leukemic patients,
patients, sites
sites of
of extramedul-
extramedul­ Hemorrhages
Hemorrhages in in the
the subhyaloid
subhyaloid space space are are boat
boat shaped
shaped

lary
lary leukemic
l e u k e m i c infiltration
infiltration have have beenb e e n examined
e x a m i n e d more
more and
and may
may break
break into into the
the vitreous,
vitreous, thus
thus obscuring
obscuring visualiza-
visualiza­

closely because they

closely because they maymay act
act as as reservoirs
reservoirs for for proliferation
proliferation tion
tion of the poste~ior
of the posterior pole. pole. Subretinal
Subretinal hemorrhages
hemorrhages are are

of
of leukemic
leukemic cells cells and and eventual
eventual systemic
systemic relapse.
relapse. These These rare.
rare.

sites have been

sites have been considered
considered "pharmacologic
"pharmacologic sanctuaries,"
sanctuaries," Kuwabara
Kuwabara and and Aiell0
Aiello
7878 first
first described
described nodularnodular retinal
retina!

relatively unaffected
relatively unaffected by by systemi~
systernis chemotherapy
chemotherapy and and re- re­ infiltrates,
infiltrates, looking
looking much much like like miliary
miliary nodules,
nodules, associated
associated

quiring
quiring separate
separate radiotherapy.
radiotherapy.68-71 Although
68-71
Although the the CNS CNS is is with
with local
local necrosis
necrosis and and hemorrhage
hemorrhage in in aa patient
patient with with

one
one of of the
the most
most frequent
frequent sites sites ofof relapse
relapse after
after initial
initial chronic
chronic myelogenous
myelogenous leukemia, leukemia, and and Schachat
Schachat and and col-col­

induction
induction of of remission,72
remission,
72
it
it isis now
now generally
generally accepted
accepted leagues 79 described similar
Ieagues?? described similar leukemic
leukemic infiltrates
infiltrates in in upup to to

that the
that the eye,
eye, like
like thethe CNS,
CNS, is is aa pharmacologic
pharmacologic sanctuary,
sanctuary, 3%
3 % of
of newly
newly diagnosed
diagnosed ALL ALL and and AML
AML cases. cases. These
These infil-
infil­

requiring radiation
requiring radiation for for elimination
elimination of of tumor
tumor cells.
cells.
65 ,73
55, 73
trates
trates have
have been been foundfound to to occur
occur in in association
association with with ele-ele­

Ocular
Ocular involvement
involvement in in leukemia
leukemia occursoccurs either
either because
because vated
vated leukocyte
leukocyte counts counts with with a a high
high proportion
proportion of of blast
blast

of
of infiltration
infiltration of of leukemic
leukemic cells cells or
or because
because of of various
various cells 80 and have
cells'" and have beenbeen associated
associated with with fulminant
fulminant diseasedisease

hemorrhagic phenomena,
hemorrhagic phenomena, and practically any
and practically any part
part of of the
the and
and early
early demise.
demise.

eye
eye can
can be be involved.
involved. The The ocular
ocular abnormalities
abnormalities are are de- de­ Peripheral
Peripheral retinal retina! microaneurysms
microaneurysms are are a a feature
feature of of

scribed next, according

scribed next, according to to the the part
part of of the
the eye
eye involved.
involved. chronic
chronic leukemias,
leukemias, especially
especially chronic
chronic myelogenous
myelogenous leuke- leuke­

Recognizing
R e c o g n i zi n g leukemic
l e u k e m i c involvement
i n v o l v e m e n t of
of the
the eyeeye is is im-
im­ mia.
mia.
81 Prolonged
81
Prolonged leukocytosis
leukocytosis seems seems to to bebe necessary
necessary for for

portant because
portant because it it may
may present
present the the first
first manifest
manifest signssigns of of the
the development
development of of peripheral
peripheral retinalretina! microaneurysms,
microaneurysms,

extramedullary
extramedullary relapse, relapse, and and promptprompt identification
identification and and and
and this
this may
may be be caused
caused by by increased
increased lateral
lateral pressure
pressure on on

FIGURE
F I G U R E 48-2.
48-2. A and B,
A and B, Fundus
Fundus photographs
photographs in
in a
a patient
patient with
with leukemia.
leukemia. Flame-shaped
Flame-shaped nerve
nerve fiber
fiber layer
layer hemorrhages
hemorrhages and
and large
large subhyaloid
subhyaloid

hemorrhages
hemorrhages can can be
be seen.
seen. (See
(See color
color insert.)
insert.)
m) CHAPTER48:
CHAPTER 48: MASQUERADE
MASQUERADE SYNDROMES:
S Y N D R O M E S : MALIGNANCIES
MAUGNANCIES

the
the walls
walls of
of vessels
vessels as
as aa consequence
consequence of of increased
increased viscosity.
viscosity. tologic
tologic relapse
relapse at at the
the time
time of of iris
iris infiltration,
infiltration, cases cases have
have

Retinal
Retinal neovascularization,
neovascularization, similar
similar to
to the
the sea-fan
sea-fan configu-
configu­ been
been reported
reported in in which
which involvement
involvement of of thethe iris
iris may
may be be

ration
ration seen
seen inin sickle
sickle cell
cell anemia,
anemia, is
is a
a rare
rare complication
complication the
the first,
first, oror even
even thethe onlyonly sitesite of
of relapse;
relapse; again, again, the
the

that
that has
has alSo
also been
been found
found in in patients
patients with
with chronic
chronic myelog-
myelog­ anterior
anterior segmentsegment has has been
been postulated
postulated as as a a "pharmaco-
"pharmaco­

enous
enous leukemia;
leukemia; it it is
is associated
associated with
with peripheral
peripheral vascular
vascular logic
l o g i c sanctuary"
sanctuary" for
for leukemic
leukemic cells. c e ll s . Bremner
B r e m n e r and
and

occlusion
occlusion and
and capillary
capillary dropout.
dropout. This
This has
has been
been related
related to
to Wright,99
Wright,
99
for
for example,
example, report
reporta a case
case with
with the the typical
typical symp-
symp­

higher
higher white
white blood
blood cellcell counts
counts and,
and, in
in one
one case,
case, with
with toms
toms of of iridocyclitis
iridocyclitis and and a a hypopyon,
hypopyon, with with typical
typical "gluti-
"gluti­

increased
increased number
number of of circulating
circulating platelets.
82-84
platelets.82-84 nous"
nous" leukemic
leukemic cells cells in
in thethe crypt
crypt ofof the
the irisiris asas the
the only
only

site
site of of leukemic
leukemic relapse,
relapse, in in which
which symptoms
symptoms resolved resolved with
with

Uveal
Uveal Tract
Tract local
local corticosteroid
corticosteroid therapy,
therapy, only only toto recur.
recur. Gruenewald
Gruenewald

and
and associates
100 and Ninane
associates'?" and Ninane and and colleagues
colleagues º also
1 101 also report
1
report

CHOROID
CHOROID cases
cases withwith thethe anterior
anterior segment
segment as as the
the first
first site
site ofof relapse.
relapse.

The
The choroid
choroid is is commonly
commonly infiltrated
infiltrated withwith leukemic
leukemic cells,
cells, Tabbara
Tabbara and and Beckstead
Beckstead
94
94
report
report thethe case
case of of aa 3-month-old
3-month-old

although
although thisthis may
may gogo undetected
undetected clinically.
clinically. InIn fact,
fact, histo-
histo­ infant
infant with with bilateral
bilateral eyeeye redness
redness andand anterior
anterior chamber
chamber

pathologically, the
pathologically, the choroid
choroid may may be be the
the most
most commonly
commonly pseudohypopyon
pseudohypopyon as as the
the first
first detected
detected sign sign of of acute
acute pro-
pro­
affected
affected partpart of of the
the eye,57,75
eye,67,
75
with
with thethe most
m o s t striking
striking monocytic
monocytic leukemia.leukemia.

changes
changes observed
observed in in acute
acute leukemias,
leukemias, especially
especially ALL.75
ALL.75

When
When visible
visible clinically,
clinically, these
these leukemic
leukemic choroidal
choroidal infil-infil­ VITREOUS
YITREOUS

trates
trates may
may manifest
manifest as as bilateral
bilateral serous
serous detachment
detachment of of the
the Leukemic
Leukemic involvement
involvement of of vitreous
vitreous may may present
present with with a a

retina,57
retina,
67
or
or as
as single
single large
large choroidal
choroidal masses
masses and and overlying
overlying vitreous
vitreous hemorrhage
hemorrhage in in the
the presence
presence of of retinal
retinal changes.
changes.

serous
serous retinal
.retinal detachment
detachment in in adults
adults with
with chronic
chronic myeloge-
myeloge­ Infiltration
Infiltration of of the
the vitreous
vitreous withwith leukemic
leukemic cells cells without
without

nous leukemia.
nous
85 This choroidal
leukemia.85 This choroidal involvement
involvement can can also
also hemorrhage
hemorrhage is is uncommon,
uncommon, most most likely
likely reflecting
reflecting the the bar-
bar­

induce
induce secondary
secondary changes
changes in in the
the RPE
RPE including
including atrophy,
atrophy, rier
rier function
function of of the
the intact
intact internal
internal limiting
limiting membrane.
membrane.78
78
hypertrophy, and
hypertrophy, and hyperplasia,
hyperplasia, and and occasionally
occasionally giving
giving rise
rise However,
However, such such cases
cases have
have been
been reported,
reported, both both in in patho-
patho­

to aa leopard
to leopard spot spot pattern.
pattern.
57
67
This
This maymay occur
occur because
because of of logic
logic studies
57 and in
studies67 and in case
case reports.
reports. Reese
Reese and and Guy Guy men-
men­

either primary invasion

either primary invasion or or compressive
compressive involvement
involvement of of tion
tion vitreous
vitreous opacities
opacities in in one
one ofof their
their cases,102
cases,
102
and
and Swartz
Swartz

the choriocapillaries
the choriocapillaries by by neoplastic
neoplastic cells.
cells.
85
86
Fluorescein
Fluorescein an- an­ and
and Schumann
103 report the
Schumann-?" report the case
case of of a a patient
patient with with ALL,
ALL,

giographic
giographic changes
changes in in patients
patients withwith choroidal
choroidal infiltration
infiltration treated
treated with
with several
several cycles
cycles of of chemotherapy,
chemotherapy, who who thenthen

and
and overlying
overlying serous
serous retinal
retinal detachment
detachment of of the
the retina
retina presented
presented with with unilateral,
unilateral, progressive,
progressive, painless
painless loss loss ofof

show
show a a multitude
multitude of of RPE
RPE leakage
leakage poinrs
poinfs inin the
the early
early phase
phase vision
vision found
found to to be
be caused
caused by by dense
dense cellular
cellular infiltration
infiltration of of

of
of the
the angiogram,
angiogram, described
described as as a
a milky-way
milky-way pattern.
85 With
pattern.85 With the
the vitreous,
vitreous, withwith clumping
dumping of of cells
cells andand vitreous
vitreous fibrils
fibrils

time, these
time, these leakage
leakage points
points become
become more more diffuse,
diffuse, and
and dye
dye into
in.to opaque
opaque sheets
sheets as as the
the only
only sign
sign of of leukemic
leukemic involve-
involve­

leaks into
leaks in.to the
the subretinal
subretinal space.
space. ment
ment of of the
the CNS.
CNS. This
This patient
patient diddid notnot receive
receive CNS CNS pro-pro­

phylactic
phylactic radiation,
radiation, but but relapse
relapse inin the
the eye
eye can
can occur
occur even
even

IRIS AND
IRIS A N D ANTERIOR
ANTERIOR SEGMENT
SEGMENT after
after such
such radiation
radiation has has been
been given,
given, as as seen
seen in in the
the case
case

Anterior
Anterior segment
segment involvement
involvement in in leukemias
leukemias is is unusual
un.usual described
described by by Bremner
Bremner and and Wright.
Wright.
99
99
Diagnosis
Diagnosis is is made
made by by

but has
but has received
received increasing
increasing attention
attention as as a a site
site ofof extra-
extra­ aa PPV
PPV with
with cytologic
cytologic examination
examination of of the
the vitreous.
vitreous. Infec-
Infec­

medullary relapse.
medullary r e l a p s e . Most
M o s t cases
c a s e s of
of anterior
a n t e ri o r segment
segment tions
tions are
are a a distinct
distinct possibility
possibility in in patients
patients with with leukemia
leukemia

involvement
involvement have have had had acute
acute lymphoblastic
lymphoblastic leukemia,leukemia, al- al­ because
because of of the
the leukemic
leukemic statestate itself
itself andand the the treatment
treatment

though cases
though cases withwith CLL CLL and and AML AML have have also also been
been re-re­ received,
received, and and so so endophthalmitis
endophthalmitis may may have
have to to be
be ex-ex­

ported. 87
ported. -89 Patients
87-89 Patients characteristically
characteristically present present with with unilat-
unilat­ cluded
cluded by by a a Gram
Gram stain
stain andand culture
culture of of the
the vitrectomy
vitrectomy

eral
eral or bilateral symptoms
or bilateral symptoms of of acute
acute iridocyclitis
iridocyclitis with with specimen
specimen for for bacteria
bacteria and and fungi.
fungi. In In addition,
addition, opportunis-
opportunis­

conjunctival
conjunctival injection,
injection, iritis,
iritis, hypopyon,
hypopyon, pseudohypopyon,
pseudohypopyon, tic
tic infections
infections commonly
commonly seen seen inin patients
patients with with AIDS,
AIDS, suchsuch

or
or spontaneous
spontaneous hyphema. hyphema.
55 , 88, 90-93 The
55, 88, 9 93
0- The pseudohypopyon
pseudohypopyon as
as cytomegalovirus
cytomegalovirus retinitis,
retinitis, other
other acute
acute necrotizing
necrotizing her- her­

has, in
has, in some
sorne case
case reports,
reports, beenbeen defined
defined as as "shaggy,
"shaggy, irreg-
irreg­ petic
petic infections,
infections, andand toxoplasmosis,
toxoplasmosis, may may appear
appear in in pa-
pa­

ular, free-floating
ular, free-floating material"
material" that that fails
fails to
to settle
settle inferiorly
inferiorly tients
tients with
with leukemia
leukemia who who areare immunosuppressed.
immunosuppressed.

and
and has has a a characteristic
characteristic creamy-white
creamy-white color. color.
94 It
94
It consists
consists

of
of leukemic
leukemic cells cells that
that have
have infiltrated
infiltrated into into thethe anterior
anterior Optic
Optic Nerve
Nerve
chamber
chamber and and maymay initially
initially respond
respond to to topical
topical or or periocu-
periocu­ Leukemic
Leukemic optic
optic nerve
nerve infiltration
infiltration occurs
occurs primarily
primarily in in chil-
chil­

lar
lar steroids,
steroids, although
although the the infiltrate
infiltrate recurs.
recurs. Diffuse
Diffuse or or nod-
nod­ dren
dren with
with acute
acute leukemias
leukemias and and especially
especially ALL.73
ALL.7 This
3
This isis a
a

ular iris
ular iris involvement
involvement may may occur.
occur. Diffuse
Diffuse involvement
involvement particularly
particularly worrisome
worrisome finding;
finding; like
like vitreous
vitreous involvement,
involvement,

presents as
presents as discoloration
discoloration with with a a whitish
whitish graygray filmfilm and
and it
it implies
implies CNS
CNS disease.
disease. Involvement
Involvement of of the optic ne~ve
the optic ne�ve

heterochromia iridis.
heterochromia iridis. Nodular
Nodular involvement
involvement is is seen
seen asas ill-
ill­ can
can be
be pre1aminar,
prelaminar, with with primarily
primarily invasion
invasion of of the
the optic
optic

defined
defined densities
densities extending
extending usually usually to to the
the pupillary
pupillary mar-mar­ nerve
nerve head,
head, or
or retrolaminar.
retrolaminar. Prelaminar
Prelaminar invasion
invasion is is associ-
associ­

gin. 95 Glaucoma may

gin.95 Glaucoma may occur
occur withwith these
these findings
findings as as aa result
result ated
ated with
with aa fluffy,
fluffy, edematous
edematous appearance
appearance to to the
the nervenerve

of
of leukemic
leukemic infiltration
infiltration of of the
the trabecular
trabecular meshwork,
meshwork, or or as
as head
head with
with moderate
moderate edema edema andand hemorrhage.
hemorrhage. The The visual
visual

angle-closure glaucoma
angle-closure glaucoma following
following choroidal
choroidal infiltration
infiltration acuity
acuity may
may bebe altered
altered onlyonly minimally,
minimally, or or it
it may
may bebe signifi-
signifi­

and
and hemorrhage.
94 9 93 Diagnosis is
hemorrhage.":,96-98 Diagnosis
6- is established
established by by ante-
ante­ cantly impaired
cantly impaired if if edema
edema andand hemorrhage
hemorrhage extend extend into in.to

rior
rior chamber
chamber paracentesis
paracentesis with with cytologic
cytologic examination
examination of of the
the macular
macular area.
area.
73
73
Retrolaminar
Retrolaminar invasion,
invasion, on on thethe other
other

the
the aqueous
aqueous humor.
humor.
94 Low-dose,
94
Low-dose, local local anterior
anterior segment
segment hand,
hand, is
is associated
associated with with aa profound
profound decrease
decrease in in vision
vision

irradiation
irradiation is is the
the treatment
treatment of of choice.
94 95
choice.?",95 and
and moderate
moderate to to pronounced
pronounced disc clise elevation
elevation andand some sorne

Although
Although most most patients
patients have have had had meningeal
meningeal or or hema-
herna- edema
edema and
and hemorrhage.
hemorrhage. This This must
must bebe distinguished
distinguished from from
 CHAPTER 48: MASQUERADE
C H A P T E R 48: M A S Q U E RA D E SYNDROMES:
S Y N D R O M E S : MALIGNANCIES
MAUGNANCIES

papilledema due to
papilledema due to increased
increased intracranial pressure, and
intracranial pressure, and able to relate
able to relate the
the retinal
retinal findings
findings ofof leukemia
leukemia toto. hemato­
hemato-
this
this is
is done
done by by aa lumbar puncture. Differentiation
lumbar puncture. Differentiation is is logic status,80,
logic
80 116
Culler 117 reports
status, , 116 Culler'!? reports aa correlation
correlation between
between
important because infiltration
important because infiltration of of either type of
either type of leukemic
leukemic low red
low red cell
cell and
and platelet
platelet counts
counts and
and retinal
retinal hemorrhages,
hemorrhages,
optic
optic neuropathy
neuropathy responds
responds dramatically
dramatically to to radiation
radiation ther­
ther- and the
and the relationship
relationship between
between low low platelet
platelet counts
counts and
and
apy,
apy, whereas papilledema does
whereas papilledema does not.not. InIn fact, with retrolam­
fact, with retrolam- hemorrhages is
hemorrhages is confirmed
confirmed by by two
two more
more recent
recent prospec­
prospec-
inar
inar infiltration, urgent institution
infiltration, urgent institution of radiation therapy
of radiation therapy isis tive studies. 118 ,119
tive studies.i": 119
Kincaid and
Kincaid Green67 have
and Green67 have suggested
suggested that
that
necessary
necessary to restore vision
to restore vision and and to to prevent
prevent permanent
permanent the relationship
the relationship between
between retinal
retinal findings
findings and
and the
the blood
blood
visual
visual loss.
loss. count may
count may bebe inconclusive
inconclusive because
because thethe blood
blood profile
profile in
in
Since the recognition
Since the recognition of the CNSas
of the CNS as a pharmacologic
a pharmacologic these patients
these patients varíes
varies during
during the
the disease
disease course,
course, and
and the
the
sanctuary,
sanctuary, and the eye
and the eye asas an
an extension
extension of this pharmaco­
of this pharmaco- appearance of
appearance of the
the retinal
retinal findings
findings may
may be
be delayed,
delayed, corre­
corre-
logically privileged site,68,
logically privileged site."' 70, 104 it
70, 104
it is now widely
is 110w widely accepted
accepted lating better
lating better with
with thethe blood
blood cell
cell counts
counts of
of approximately
approximately
that the
that the posterior
posterior polepole of the eye
of the eye should
should be be included
included inin a month
a month earlier.
earlier.
radiation therapy
radiation therapy for the prophylaxis
for the prophylaxis of of CNS
CNS leukemic
leukemic

involvement.65
involvement.
65
Thus
Thus thethe frequency
frequency of of optic nerve head
optic nerve head Treatment and Prognosis
Treatment and Prognosis
involvement
involvement in in leukemias
leukemias is is decreasing
decreasing with with the
the use
use of
of The treatment
The treatment and and prognosis
prognosis for for signs
signs andand symptoms
symptoms in in
prophylactic posterior
próphylactic posterior pole
pole radiation
radiation and more aggressive
and more aggressive leukemia were described
leukemia were described in in preceding
preceding sections.
sections. As long-
As long­
systemic and
systemic and intrathecal
intrathecal chemotherapy.73
chemotherapy.73 term survival
term survival andand even
even cure
cure ofof leukemia
leukemia become become a a possi­
possi-
bility, increasing attention
bility, increasing attention is is being
being paidpaid to to the
the ocular
ocular
Orbital
Orbital and Lid lnvolvement
and Lid Involvement manifestations, both
manifestations, both asas aa sign
sign of
of extramedullary
extramedullary disease disease
Approximately 11 % of children with unilateral proptosis
Approximately 1 1 % of children with unilateral proptosis relapse, and
relapse, and in in terms
terms ofof vision
vision preservation
preservation to to enhance
enhance
have some
have sorne form
form of of acute
acute leukemia,105
leukemia,
105
and
and leukemia
leukemia ac- ac­ quality of
quality of life.
life. Although,
Although, even even with
with irradiation
irradiation and and in­in-
counts
counts for for 2%
2 % to to 6%
6% of of orbital tumors of
orbital tumors of childhood.
childhood.''"
106 trathecal MTX,
trathecal MTX, visual
visual outcome
outcome is is not
not always
always good,
good, new new
Orbital
Orbital involvement
involvement of the eyes
of the eyes occurs
occurs as as a result of
a result of either
either studies evaluating the
studies evaluating the ocular
ocular morbidity
morbidity of of acute
acute leuke­
leuke-
tissue infiltration
tissue infiltration by by leukemic
leukemic cells cells or hemorrhage. Thus,
or hemorrhage. Thus, mias have
mias have shown
shown surprisingly
surprisingly goodgood results
results in in both
both AMLAML
patients may
patients may have
have infiltration
infiltration of the lid,
of the lid, orbit,
orbit, oror lacrimal
lacrimal and
and ALLALL parients.P?
patients,120, 121
121
as prophylactic
as prophylactic and and treatment
treatment
gland, proptosis, diplopia,
gland, proptosis, motility disturbances,
diplopía, motility disturbances, ecchy-ecchy­ approaches
approaches for for extramedullary leukemia continue
extramedullary leukemia continue to to be
be
mosis,
m o s i s , lid
lid h hemorrhage,
e m o r r h a g e , or retrobulbar h
or retrobulbar hemorrhage,
emorrhage, refined, based
refined, based on 011' the
the type
type ofof leukemia,
leukemia, previous
previous treat­
treat-
which may
which may extend
extend forward
forward into the subconjunctival
into the subconjunctival space. space. ments, marrow
ments, marrow relapse,
relapse, andand CSFCSF profile.
profile.122-124
122-124
Develop-
Develop­

In
In an undiagnosed patient,
an undiagnosed patient, biopsy
biopsy may may be be required
required for for ment of
ment of the
the concept
concept of of certain
certain extramedullary
extramedullary sites, sites, in­
in-
diagnosis
diagnosis of of leukemia,
leukemia, and and in tlqe immunocompromised
in the immunocompromised cluding the
cluding the CNSCNS and and the the eye,
eye, as as p pharmacologic
harmacologic

leukemic
leukemic patientpatient with with proptosis
proptosis (especially
( especially one one onon che-
che­ sanctuaries
sanctuaries has has been
been aa significant
significant step
step in in decreasing
decreasing ocu­ ocu-
motherapy),
motherapy), infectioninfection must must be be excluded. 107 Orbital leuke­
excluded.'"? Orbitalleuke- lar as
lar as well
well as as systemic morbidity.65,
systemic morbidity. 80,, 125, 126 The
55, 80 125, 126
The mostmost
mia
mia maymay also present with
also present with infiltration
infiltration of of any
any other
other orbital
orbital striking
striking example
example of of this
this isis ALL,
ALL, which
which now now hashas a a 990%
0%

structure
structure including
including the the lacrimal
lacrimal gland,
gland, the the rectus
rectus mus­
mus- remission rate
remission rate aand
nda a 50%
5 0 % cure rate. 125 , 126
cure rate.l'": 126

eles, the
cles, the dermis,
dermis, and and the the lacrimal
lacrimal draining
draining system.
68 108
system.68·, 108

Granulocytic
Granulocytic sarcoma,sarcoma, or or chloroma,
chloroma, a variant of
a variant my-
of my­ MALIGNANT
M A LI G N A N T MELANOMA
elogenous
e l o g e n o u s leukemia,
l e u k e m i a , classically
classically pre presents with tumor
sen ts with tumor
masses
masses in in the
the orbit.
orbit. These
These may may be be unilateral
unilateral or bilateral,
or bilateral, Definition
Definition

and
and theythey have
have a a greenish
greenish appearance
appearance on on gross pathologic
gross pathologic Malignant melanoma of
Malignant melanoma the eye
of the eye is
is aa malignant
malignant melano­
melano-
examination
examination because because of of the presence of
the presence of the
the enzyme
enzyme mye­mye- cytic stromal
cytic proliferation of
stromal proliferation of the
the choroid,
choroid, the
the ciliary
ciliary body,
body,
loperoxidase.
Ioperoxidase.l'" A
109 A chloroma
chloroma may may manifest
manifest at at any time in
any time in or the
or the iris.
iris. Malignant
Malignant melanoma
melanoma of of the
the choroid
choroid and
and
the
the course
course of of myelogenous
myelogenous leukemia, leukemia, sometimes preced-
sometimes preced­ ciliary body
ciliary body isis the
the most
most common
common primary
primary intraocular
intraocular
ing hematologic signs.
ing hematologic signs. In myeloproliferative disorders,
In myeloproliferative disorders, it it malignancy.
malignancy.

may be
may be aa harbinger
harbinger of of a blast crisis
a blast crisis and transformation
and transformation

into
into AML.AML.ll0 110
Thus,
Thus, in in thethe presence
presence of of granulocytic
granulocytic sar- sar­ History
History

coma,
coma, the the ophthalmologist
ophthalmologist must must be be alerted
alerted to to the
the immi-
immi­ Melanoma was considered to be the most C01nmon malig-
Melanoma was considered to be the most common malig­

nent appearance
nent appearance of AML. These
of AML. tumors have
These tumors have aa poor
poor nancy of
nancy of the
the eye
eye up
up to to the
the 1960s, when it
1 9 6 O s , when it was
was thought
thought toto
prognosis, with
prognosis, with aa survival
survival of between 11 and
of between and 30 months
30 months have an
have an incidence
incidence around
around 20 20 times
times greater
greater than
than that
that of
of
after
after onset
onset ofof ocular
ocular signs
signs andand symptoms.
l1l
symptoms. n , 112
i,
112
metastatic tumors. 127
metastatic tumors.1 27
However, with
However, with increased
increased survival
survival of
of
cancer patients
cancer patients andand withwith the
the proliferation
proliferation of of medica!
medical
Other
Other Unusual Manifestations
Unusual Manifestations literature, it
literature, it carne
came to to be
be recognized
recognized that that malignant
malignant mela­
mela-
Leukemia
Leukemia can present with
can present with infiltration
infiltration and hemorrhage
and hemorrhage nomas, although
nomas, although the the most
most common
common primary primary eye
eye malig­
malig-
into practically any
into practically part of
any part the eye,
of the eye, and thus aa number
and thus number of of nancy, are in
nancy, are in fact,
fact, much
much less
less common
common than than metastatic
metastatic
uncommon manifestations
uncommon manifestations have
have been
been reported
reported in in thethe tumors of
tumors of the
the eye.
eye.
literature,
literature, including
including corneal ring ulcer
corneal ring ulcer inin AML,
AML,113 113
Sjo-
Sjó­

gren's
gren ' s syndrome with lacrimal
syndrome with lacrimal gland
gland enlargement in
e n l a r g e m e n t in Epidemiology
Epidemiology
CLL,114
CLL,
114
and
and anterior
anterior segment
segment ischemia
115 in CML.
ischemia!" in CML. Melanomas are the most prevalent primary eye malignan-
Melanomas are the most prevalent primary eye malignan­

cies, with
cies, with posterior
posterior melanomas
melanomas occurring
occurring atat aa higher
higher
Pathogenesis
Pathogenesis frequency than
frequency than irisiris melanomas.
melanomas. Iris
Iris lesions
lesions account
account for
for
Various studies
Various have attempted
studies have to relate
attempted to relate the
the pathologic
pathologic only 33.3%
only to 12.5%
. 3 % to of all
1 2 . 5 % of all surgically
surgically eexcised
xcised mmelano-
elano­

findings
findings in the eyes
in the eyes of
of leukemic patients with
leukemic patients with the
the overall
overall mas128-132; they
mas128-132; they occur
occur at at an
an average
average age
age of
of between
between 40
40 and
and
systemic changes.
systemic Although most
changes. Although most authors have been
authors have been un-
un- 50 years 128, 132-136
50 years!"' 132-135
and with
and with equal
equal incidence
incidence inin men
men and
and
 CHAPTER 48: MASQUERADE
M A S Q U E R A D E SYNDROMES:
lfijJ . C H A P T E R 48: S Y N D R O M E S : MALIGNANCIES
MAUGNANCIES

women. 12
women. 8-130, 132, 135, 136 They
12
B-
13
They occur
o, occur more
132•
more in
135·
in whites
136
whites and and in in ber
ber and and pigment
pigment on on the the anterior
anterior surface
surface of of the
the lens,
lens, this
this

patients
patients with
with light
light irides
írides than
than inin Asians
Asians and
and blacks.
blacks.
128 , 134, 137 128· 134• 137
condition
condition can can masquerade
masquerade as as uveitis.
uveitis.

:Most
Most iridic
iridic melanomas
melanomas (and
(and also
also nevi)
nevi) arise
arise from
from the the Choroidal
Choroidal melanomas melanomas present present with with symptOlns
symptoms of of visual
visual

inferior
inferior portion
portion ofof the
the iris,
iris, more
more often
often peripherally
peripherally and and loss, photopsias,
loss, photopsias, and and visual
visual fieldfield defects,
defects, althoughalthough they they
temporally.128,
temporallv-": 134, 136 134, 135 may
may be be asymptomatic.
asymptomatic. Unusual Unusual presentations,
presentations, including including

Choroidal
Choroidal melanomas
melanomas occur occur at at an
an average
average ageage that
that is is severe
severe pain,pain, suggest
suggest a a diagnosis
diagnosis other other than than that that of of choroi-
choroi­

about
about 101 O years
years above
above thatthat for
for iris
iris melanomas.
melanomas. They They are are dal
dal melanoma;
melanoma; but but painpain maymay occuroccur in in melanOlnas
melanomas associ- associ­

eight
eight times
times more
more common
common in in whites
whites than
than blacks
blacks
l38 , 139 and
and
138• 139
ated
ated with with inflammation,
inflammation, massive massive extraocular
extraocular extension, extension,

six
six times
times more
more common
common in in whites
whites than
than inin some
sorne AsianAsían or
or neovascular
neovascular glaucoma. glaucoma. An An ocular
ocular historyhistory of of anan oldold

populations.140,
populations. º· 141
14 141
nevus,
nevus, or or systemic
systemic nonocular
nonocular malignancies
malignancies may may be be helpful
helpful

in
in establishing
establishing a a diagnosis,
diagnosis, but but oneone must
must also also remember
remember

Clinical
C li n ic a l Characteristics
Characteristics that
that 6% 6 % to to 10% 1 0 % of of melanoma
melanoma patients patients have have another
another pri- pri­

In
In a a high
high proportion
proportion of of patients,
patients, iris iris melanomas
melanomas arise arise mary
mary neoplasm.
neoplasm.
152 , 153
152· 153

from
from pre-existing
pre-existing lesions lesions that that suddenly
suddenly undergo undergo active active Examination
Examination is is ofof vital
vital importance
importance in in the
the diagnosis,
diagnosis, as as

growth.
growth.
129 , 130,º· 132, 142 They
129, 13 132•
They present
142
present in in three
three patterns-ring,
patterns-ring, it
it has
has been
been reported
reported that that indirect
indirect ophthalmoscopy
ophthalmoscopy leads leads

tapioca,
tapioca, and and diffuse
diffuse melanomas.
melanomas. Diffuse Diffuse melanomas
melanomas pre- pre­ to
to a a correct
correct diagnosis
diagnosis of of melanoma
melanoma in in greater
greater than than 95%95%

sent
sent with
with unilateral
unilateral acquired acquired heterochromia
heterochromia and and second-
secorid­ of
of cases.
cases.
154 Visual
154
Visual fields fields are are not not helpful
helpful in in ruling
ruling out out

ary
ary glaucoma.
glaucoma. Although Although they they have
have the the highest
highest likelihood
likelihood benign
benign lesions,147,
lesions,
147,
155 as
155
as melanomas
melanomas have have no no characteristic
characteristic

of
of Inetastasizing,
metastasizing, they they alsoalso havehave an an excellent
excellent prognosis.
prognosis.':":,
132 visual
visual field
field changes.
changes. Scleral Scleral transillumination
transillumination is is blocked
blocked

142-144 Ring
142-144
Ring melanomas involve more than two thirds of
melanomas involve more than two thirds of by
by melanomas
melanomas but but not not by by choroidal
choroidal effusions.
effusions. MelanomasMelanomas

the
the angle
angle circumferentially,
circumferentially, and and they
they are are associated
associated with with appear
appear classically
classically as as pigmented,
pigmented, dome- dome- or or collar
collar button-
button­

secondary
secondary glaucoma. glaucoma. Many Many are are diagnosed
diagnosed incorrectly
incorrectly be- be­ shaped
shaped tumors tumors with with associated
associated exudative
exudative retinal retinal detach-
detach­

cause
cause of of failure
failure to to recognize
recognize an an infiltrating
infiltrating pigmentedpigmented ment
ment that that may may involve
involve the the macula
macula and and thus thus decrease
decrease

lesion
lesion as as a a cause
cause of of refractory
refractory glaucoma.
glaucoma. Tapioca Tapioca melano- melano­ vision
vision (see (see Fig. Fig. 48-3E).
48-3E). Although
Although only only a a minority
minority of of cho-
cho­

mas 145 are lightly

mas!" are lightly pigmented
pigmented or or nonpigmented
nonpigmented multifocal multifocal roidal
roidal melanomas
melanomas have have the the collar-button
collar-button configuration,
configuration,

nodules
nodules that that project
project into into the the anterior
anterior chamber.chamber. These These breaks
breaks in in Bruch's
Bruch's membrane membrane are are rarely
rarely seen seen with with any any

lesions
lesions are are sometimes
sometimes associated associated with with glaucoma.
glaucoma. They They other
other type type of of lesion.
lesion.

were
were initially
initially thought thought of of asas benign,
benign, but but now now it it isis recog-
recog­ Other
Other signs signs include
include a a deposition
deposition of of lipofuscin
lipofuscin at at the
the

nized that
nized that somesorne can can be be categorized
categorized histologically
histologically as as mela-
mela­ level
level of of the
the RPE,RPE, seen seen as asa ann orange
orange pigment;
pigment; a a tumor
tumor with with

nomas,142
nomas,
142
and
and metastatic
metastatic disease disease has has bet:n
been reported.
reported.
146
146
an
an elevated,
elevated, globular globular shape; shape; exudative
exudative retinal retinal detachment
detachment

Clinical
Clinical differentiation
differentiation between between malignant
malignant and and benign
benign with
with a a large
large tumor;tumor; and and tumor
tumor pigmentation
pigmentation (although (although

lesions
lesions is is based
based on on clinical
clinical features.
features. A A lesion
lesion is is considered
considered nearly
nearly one one fourthfourth of of tumors
tumors are are nonpigmented).
nonpigmented). Some Sorne

malignant
malignant if if itit is
is 33 mm
mm or or greater
greater in in diameter
diameter and and 1 1 mm
mm large
large melanomas,
melanomas, especially especially those those involving
involving the the ciliary
ciliary

or
or greater
greater in in thickness
thickness and and has has three
three of of the
the following
following five five body, may
body, may have have prominent
prominent scleral scleral vessels
vessels called called sentinel
sentinel

features
features
l47 , 148: secondary
147• 148:
secondary glaucoma, glaucoma, secondarysecondary cataract, cataract, vessels
vessels (see ( see Fig.Fig. 48-3C).
48-3 C) .

photographic documentation
photographic documentation of of growth,
growth, ectropion
ectropion irides, írides, Uncommon
Uncommon presentations presentations include include diffuse diffuse melanoma
melanoma

and
and prominent
prominent vascularity. vascularity. Notable Notable tumor tumor growth growth and and (less
(less than
than 5 5 mmmm thick,thick, covering
covering more more than than 25% 2 5 % of of the
the

intense
intense vascularity
vascularity have have been been cited cited as as being
being the the most most uveal
uveal tract),
tract), 156 which
156
which has has a a higher
higher rate rate of of extraocular
extraocular

reliable
reliable signs signs for for thethe diagnosis
diagnosis of of Inelanoma
melanoma of of the
the iris.iris.
149
149
spread.
spread. Melanomas
Melanomas may may also
also present
present with with significant
significant ante- ante­

However,
However, these these traditionally
traditionally acceptedaccepted conceptsconcepts are are now now rior
rior uveitis,
uveitis, especially
especially with with iridial
iridial melanomas,
melanomas, or or posterior
posterior

being challenged,
being challenged, and and a a recent
recent studystudy by by Jakobiec
Jakobiec and and inflammation
i n fl a m m a ti o n with with choroidal
c h o ro i d a l and
and ciliary
ciliary melanomas;
melanomas;

Silbert
Silbert shows shows no no correlation
correlation between between the the typetype of of lesion
lesion these
these casescases may may be be veryvery similar
similar to to thethe presentation
presentation of of

and
and the the presence
presence of of ectropion
ectropion uvea, uvea, splinting
splinting or or distor-
distor­ sarcoid,
sarcoid, tuberculous
tuberculous uveitis, uveitis, or or posterior
posterior scleritis,
scleritis, and and thethe

tion
tion of of the
the pupil,
pupil, vascularity,
vascularity, involvement
involvement of of the
the chamber
chamber choroidal
choroidal mass mass may may be be misdiagnosed
misdiagnosed as as a a granuloma.
granuloma.
145
145

angle,
angle, glaucoma,
glaucoma, or or touching
touching of of the
the cornea.
cornea.
142 This
142
This study study Fraser
Fraser and and Font,1.57
Font, 1.�
7
for
for example,
example, in in a a series
series of of 450450 eyes
eyes

concludes
concludes that that progressive
progressive growth growth or or involvement
involvement of of the
the with
with melanomas
melanomas of of the
the choroid
choroid and and ciliary
ciliary body, body, report
report

ciliary
ciliary bodybody in in a a ring
ring configuration
configuration with with progressive
progressive glau- glau­ that
that 22 22 (4.9%)
( 4 . 9 % ) hadhad ocular
ocular inflammation:
inflammation: episcleritis episcleritis (7 (7

coma
coma is is more
more commonlycommonly associated associated with with benign
benign tumors; tumors; patients),
patients), anterioranterior or or posterior
posterior uveitis
uveitis (14 ( 1 4 patients),
patients), and and

nevertheless,
nevertheless, a a lesion
lesion with with these these features
features must must still still bebe panophthalmitis
panophthalmitis or or endophthalmitis.
endophthalmitis. Haddab Haddab and and associ-
associ­

scrutinized
s c r u ti n i z e d very very c1osely.142
cl o s e l y . Tumors
Tumors with
142
with ciliary
ciliary body body
158 report the
ates!" report
ates the casecase of of a a 22-year-old
22-year-old man man with with a a de-
de­

involvement
involvement (Fig. (Fig. 48-3A-D)
48-3A-D) are are alsoalso associated
associated with with a a creased
creased visual visual acuity acuity and and signs
signs of of cells
cells and and flareflare in in the
the

higher
higher incidence
incidence of of malignancy
malignancy (although ( although neither neither episcle-episcle­ anterior
anterior chamber;
chamber; keratoprecipitates,
keratoprecipitates, posterior posterior synechiae,
synechiae,

ral dilatation
ral dilatation nor nor sector
sector cataract
cataract reflected
reflected malignancy
malignancy or or and
and roundround yellowish
yellowish nodules nodules on on thethe iris;
iris; and and elevated
elevated

ciliary
ciliary bodybody involvement)
involvement) .142 .
142
intraocular
intraocular pressure pressure and and cataract,
cataract, who who was was initially
initially treated
treated

Some
Sorne studiesstudies also also show
show that that medial
medial location
location and and pres- pres­ for
for anterior
anterior uveitis uveitis for for atat least
least 2 2 months
months before before a a diagno-
diagno­

ence
ence of of pigment
pigment dispersion dispersion onto onto the the irisiris oror angle
angle struc- struc­ sis
sis of
of ciliary
ciliary body body melanoma
melanoma was was made.
made. Similarly,
Similarly, FurdovaFurdova

tures
tures are
are the
the only
only features
features associated
a s s o c i a t e d with
with tumor
tumor and
and associates
associates
159 report
159
report the the casecase of of a a 23-year-old
23-year-old woman woman

growth.
growth.
150 According
150
According to to other
other studies,
studies, however,
however, iris iris mela-
mela­ with
with an an ultimate
ultimate diagnosis
diagnosis of of malignant
malignant melanoma melanoma pene- pene­

nomas
nomas are are more more likely likely to to be be inferiorly
inferiorly and and temporally
temporally trating
trating the the opticoptic nerve,
nerve, diagnosed
diagnosed as as intermediate
intermediate uveitis uveitis

10cated;128,
located+": 134, 136 some
134,
sorne authors
136
authors believebelieve that that a a superiorly
superiorly and
and treated
treated for for a a prolonged
prolonged period period as asa ann outpatient,
outpatient, and and

located
located lesion lesion is is unlikely
unlikely to to be be amelanoma
a melanoma
151 1:>ut
151
but may may be be later
later withwith a a PPV,
PPV, until until malignant
malignant cells cells were were found found in in

metastatic
metastatic or or a a ciliary
ciliary bodybody tumor.tumor. BecauseBecause of of clinical
clinical her
her anterior
anterior chamber chamber 4 4 months
months after after the the PPY. PPV. Thus,
Thus,

findings
findings such such as as pigment
pigment dispersion
dispersion in in the
the anterior
anterior cham- cham- Inelanomas
melanomas must must be be kept
kept in in mind
mind in in the the casecase of of such
such
 CHAPTER 48: MASQUERADE
C H A P T E R 48: M A S Q U E R A D E SYINIJIRC)MIES:
SYNDROMES: M AU
OYU""U.. G
O'I... NANCIES
: lID"1II_O"'I!\l"",ilB;;;.;Jl

FIGURE
F 48-3. A
I G U R E 48-3. A and
and B, Ciliary body
E, Ciliary body melanoma:
melanoma: NoteNote thethe mass
mass
protruding d01'vnward
protruding downward in in the
the photograph
photograph at the 12
at the o'clock posi­
12 o'clock posi-
tion. C,
tion. C, The
The dilated
dilated 'sentinel'
'sentinel' scleral blood vessel
scleral blood vessel can
can be
be seen in
seen in

the area
the area over the tumor.
over the tumor. Patients
Patients with
with unilateral,
unilateral, especially
especially sectoral,
sectoral,

cOl-uunctivitis
conjunctivitis should
should always have aa dilated
always have dilated examination
examination to to rule
rule out
out
an
an intraocular tumor. D,
intraocular tumor. D, Cataract
Cataract inin aa patient
patient with
with ciliary
ciliary body
body
melanoma. E,
melanoma. Malignant melanoma.
E, Malignant melanoma. The large, elevated
The large, elevated dome
dome

shape
shape of the tumor
of the tumor seen
seen inin this
this picture
picture isis characteristic.
characteristic. Tumors
Tumors
may also
may also show breaks in
show breaks Bruch's membrane,
in Bruch's membrane, giving
giving aa collar-button
collar-button

appearance. Although most

appearance. Although most tumors
tumors are pigmented, nearly
are pigmentecl, nearly 25%
25%
can
can bebe nonpigmented.
nonpigmented. (See (See color
color insert.)
insert.)

presentations,
presentations, especially
especially if if the patient does
the patient not respond
<loes not respond prompt one
prompt one toto rule
rule out
out choroidal hemangiomas and
choroidal hemangiomas and

to
to treatment.
treatment. metastasis.
metastasis. ·

Certain
Certain atypical
atypical findings
findings may may lead
lead to to aa diagnosis
diagnosis other
other Pigmented
Pigmented choroidal
choroidal lesions between 1.5
lesions between 1 . 5 and
and 3 Inm in
3 mm in

than
than melanoma:
melanoma: The presence of
The presence of significant hemorrhage
significant hemorrhage thickness have
thickness have been
been termed
termed intermediate
intermediate elevated pig-
elevated pig­

is
is seen
seen in
in choroidal
choroidal melanomas
melanomas only only whenwhen the the tumor
tumor has has mented choroidal
mented tumors and
choroidal tumors may have
and may have signs
signs ofof chronic-
chronic­

broken through
broken through Bruch's membrane, or
Bruch's membrane, or withwith large tumors;
large tumors; ity.
ity. These
These lesions, however, must
lesions, however, must bebe carefully
carefully observed
observed for
for

aa mass
mass lesion
lesion less
less than
than 4 4 mm with hemorrhage
mm with hemorrhage should should signs
signs ofof growth
growth byby sequential
sequential examinations, photography,
examinations, photography,

bring to
bring to mind
mind other possibilities (e.g.,
other possibilities ruptured macro
( e . g . , ruptured macro and ultrasonography, and
and ultrasonography, and for the presence
for the presence of of growth,
growth,

aneurysms,
aneurysms, disciform
disciform lesions,
lesions, and
and localized
localized choroidal
choroidal de- de­ exudative retinal detachment,
exudative retinal detachment, andand lipofuscin, which in-
lipofuscin, which in­

tachment).
tachment). Multiple
Multiple choroidal
choroidal tumors
tumors are are suggestive
suggestive of of crease the likelihood
crease the likelihood of malignancy.
of malignancy.

metastasis
metastasis or or lymphoid
lymphoid lesions; black pigmentation
lesions; black pigmentation is is sug-
sug­

gestive of
gestive of RPE
RPE hypertrophy, hyperplasia, or
hypertrophy, hyperplasia, melanocy-
or melanocy­ Pathophysiology, lmmunology, and

toma;
toma; a pink-orange color
a pink-orange color isis typical
typical of of choroidal hemangi-
choroidal hemangi­ Pathology
Pathology

oma,
oma, hemorrhage,
hemorrhage, or or osteoma;
osteoma; absence
absence of pigmentation,
of pigmentation, Sunlight
Sunlight exposure
exposure is thought to
is thought to be
be important
important in the
in the

although
although p present
r e s e n t in
in one
o n e fourth
fourth of of melanomas, must
m e l a n o m a s , must pathogenesis of iridial melanomas,16o thus
pathogenesis of iridial melanomas, thus its predilection
160
its predilection
lfD CHAPTER
CHAPTER 48:
48: MASQUERADE
MASQUERADE SYNDROMES:
SYNDROMES: MALIGNANCIES
M A LI G N A N C I E S

for
for light
light irides
irides and
and Caucasians.
Caucasians. These These lesions
lesions areare alsoalso nography.
nography. For For lesions
lesions moremore than than 3 3 mm
mm thick,
thick, combined
combined

thought
thought to to develop
develop from from preexisting
preexisting benign
benign nevi.
nevi.
142 , 161 14 2 • 161
A
A and and B B scan
sean ultrasonography
ultrasonography has has a a more
more than than 95% 95%

The
The histopathologic
histopathologic classification
classification of of iris
iris and
and choroidal
choroidal accuracy
accuracy in in thethe diagnosis
diagnosis of of choroidal
choroidal melanomas.
melanomas.
154 The
154
The

melanomas
melanomas was was originally
originally described
described by by Callender.
Callender.
162 Uveal
Uveal
162
three
three characteristic
characteristic features features on on B B scan
sean are
are an an acoustically
acoustically

melanomas
melanomas are are assigned
assigned into into the
the following
following groups
groups based
based silent
silent zonezone within
within the the melanoma,
melanoma, choroidal choroidal excavation,
excavation,

on
on their
their histopathologic
histopathologic features: features: spindle
spindle A, A, spindle
spindle B, B, and
and shadowing
shadowing in in the
the orbit.
orbit. A A scan
sean features
features include
include me- me­

fascicular,
fascicular, mixed,
mixed, epithelioid
epithelioid and and necrotic.
necrotic. NowN ow melano-
melano­ dium
dium to to low
low vitreal
vitreal echoes,
echoes, with with smooth
smooth attenuation
attenuation and and

mas
mas with
with a a spindle
spindle A A histology
histology are are regarded
regarded as as benign
benign vascular
vascular pulsations
pulsations within within the the tumor.
tumor. Ultrasonography
Ultrasonography of of

spindle
spindle cellcell nevi.
nevi.
162 , 163 This
This classification
1 6 2 • 163
classification system
system hashas been
been aa nevus,
nevus, in in contrast,
contrast, shows shows a a flat
flat lesion
lesion withwith choroidal
choroidal

shown
shown to to have
have prognostic
prognostic value value for
for ciliochoroidal
ciliochoroidal melano-
melano­ discontinuity
discontinuity on on thethe B B scan
sean andand medium
medium to to high
high internal
internal

mas,
mas, as as mortality
mortality increases
increases linearly
linearly from
from thethe spindle
spindle A A reflectivity
reflectivity on on the the A A scan.
s e a n . Intermediate
I n t e r m e d i a t e elevated
e l e v a t e d pig-
pig­

cytology
cytology to to the
the aggressive
aggressive epithelioid
epithelioid cytology.130,
cytology. º· 164-166
13 16
4-
166
mented
mented choroidalchoroidal lesions lesions (between
(between 1.5 1. 5 and
and 3 3 mmmm in in

However,
However, since since iridic
iridic lesions
lesions have
have been
been found
found to to be-
be­ height),
height), although
although difficult difficult to to diagnose
diagnose on on ultrasonogra-
ultrasonogra­

have in
have in aa much
much moremore benignbenign fashion
fashion than
than melanomas
melanomas of of phy,
phy, nevertheless
nevertheless may may exhibit
exhibit enlargement
enlargement on on sequential
sequential

the
the choroid
choroid and and ciliary
ciliary body,
body, iridic
iridic melanomas
melanomas have have beenbeen ultrasound
ultrasound exams. exams.

classified
classified into
into a a nine-part
nine-part histopathologic
histopathologic classification
classification by by Ancillary investigations
Ancillary investigations include include fluorescein
fluorescein angiogra-angiogra­

]akobiec
Jakobiec and and Silbert
Silbert
142 ; these
these investigators
142;
investigators argueargue that,that, phy,
phy, CT, CT, MRI,
MRI, indocyanine
indocyanine green green angiography,
angiography, and and radio-
radio­

based
based on on the
the clinical
clinical behavior
behavior of of iris
iris melanomas,
melanomas, a a major-
major­ active
active phosphorus
phosphorus uptake. uptake. Fluorescein
Fluorescein angiography
angiography is is of
of

ity
ity of
of these
these lesions
lesions are are inherently
inherently benign.
benign. However,
However, otherother limited
limited value.value.
154 Larger
154
Larger melanomas
melanomas may may showshow an an intrinsic
intrinsic

investigators
investigators dispute
dispute this, this, saying
saying that
that although
although luelano-
melano­ tumor
tumor "double
"double circulation"
circulation" with with extensive
extensive leakage,
leakage, late late

cytic
cytic iris
iris tumors
tumors havehave an an excellent
excellent prognosis,
prognosis, this
this isis pri-
pri­ staining,
staining, and and multiple
multiple pin-point
pin-point leaks leaks or or "hot
"h o t spots"
spots" at at

marily because
marily because of of their
their conspicuous
conspicuous location
location andand theirtheir the
the level
level of of the the RPE,155,
RPE,
155•
172 but
172
but these
these signs
signs are are by by nono

smaller
smaller size
size at
at diagnosis,167
diagnosis, and
and therefore
therefore they
167
they should
should not not means
means very very sensitive
sensitive or or specific.
specific. Fluorescein
Fluorescein angiography,
angiography,

be
be considered
considered distinct
distinct fromfrom posterior
posterior melanomas.
melanomas. however,
however, can can be be useful
useful in in differentiating
differentiating heluorrhagic
hemorrhagic

lesions
l e s i o n s (e.g.,
( e . g . , ruptured
ruptured macroaneurysms,
m a c r o a n e u r y s m s , disciform
disciform le- le­

Diagnosis
Diagnosis sions,
sions, and and localized
localized choroidal
choroidal detadlluent).
detachment).

High-resolution
High-resolution CT
1
CT 73, 174 is
173· 174
is actually
actually lessless accurate
accurate than than
Iris Melanomas
Iris Melanomas ultrasonography;
ultrasonography; MRI, nuclear MRI, nuclear MRI MRI (NMRI)
( N M RI ) ,, and and Dop-Dop­

Excluding
Excluding primary primary ciliary ciliary body body mel~nomas
melanomas with with irisiris ex-
ex­ pler
pler studies
studies still still have
have an an uncertain
uncertain role. role. Indocyanine
Indocyanine

tension
tension is is vital
vital because
because of of the the completely
completely different
different man- man­ green
green angiography
angiography may may be be useful
useful in in thethe diagnosis
diagnosis of of

agement
agement and and prognosis
prognosis of of thesethese two
two conditions.
conditions. This This is is choroidal
choroidal melanomas,
melanomas, hemangiomas, hemangiomas, and and uveal
uveal metasta-
metasta­

done
done by by indirect
indirect ophthalmoscopy
ophthalmoscopy with with scleral
scleral depression,
depression, sis. 175 A radioactive
sis.'?" A radioactive phosphorus phosphorus uptake uptake test test hashas a a low
low

scleral
scleral transillumination,
transillumination, and and gonioscopy.
gonioscopy. Ultrasonogra-
Ultrasonogra­ sensitivity
sensitivity and and specificity,16O-165,
specificity,
15
0- 176-181 and
155. 17
and fine-needle
6- fine-needle aspi-
181
aspi­

phy
phy is is done
done if if primary
primary ciliaryciliary body body melanoma
melanoma cannot cannot be be ration
ration biopsybiopsy (FNAB) (FNAB) is is neither
neither generally
generally required
required nor nor a a

excluded.
excluded. Benign Benign lesions lesions simulating
simulating malignant
malignant melanoma
melanoma good
good diagnostic
diagnostic measure measure for for determining
determining cell cell typetype or or

of
of the
the iris
iris must
must also also be be excluded.
excluded. One One study,
study, for
for example,
example, differentiating
differentiating melanoma melanoma from from nevi nevi or or other
other spindle
spindle cell cell

found
found that only 24%
that only 24% of of lesions
lesions referred
referred as as presumed
presumed iris iris tumors,
tumors, and and it it carries
carries with
with it it the
the additional
additional possible
possible risk risk
melanoma
melanoma had had beenbeen correctly
correctly diagnosed,148
diagnosed,
148
and
and the the ma-
ma­ of
of seeding
seeding of-the ofthe needleneedle tract.
tract.

jor misdiagnosed
jor misdiagnosed lesions lesions in in that that series
series were
were primary
primary cysts cysts

( 3 8 % ) and
(38%) and nevi
nevi (31 ( 3 1 %).
%). Treatment
Treatment
Photographic
Photographic documentationdocumentation of of any
any stromal
stromal melano-
melano­ Because
Because iris iris melanomas
melanomas have have a a generally
generally goodgood prognosis,
prognosis,

cytic
cytic tumor
tumor of of the
the iris
iris is
is required;
required; photographic
photographic evidence evidence observation
observation with with photos
photos every
every 3, 3, 6,
6, or
or 121 2 months,
months, de- de­

of
of progressive
p ro g r e s s i v e growth
growth or or a a diffuse
diffuse ring
ring configuration
c o n fi g u r a ti o n pending
p e n d i n g onon clinical
clinical features,
features, may may beb e all
all that
that isis war-
war­

point toward
point toward malignant
malignant melanoma.
melanoma. Similarly, Similarly, glaucoma
glaucoma ranted. 142
ranted.l''", 147, 149 Surgical
147•
Surgical intervention
149
intervention is is indicated,
indicated, with with

points toward
points toward a a malignant
malignant lesion, lesion, asas does
does thethe tendency
tendency complete
complete excisionexcision usually
usually by by sector
sector iridectomy,
iridectomy, if if the
the

of
of thethe lesion
lesion to to spread
spread beyond
beyond the the pupillary
pupillary neuroecto-
neuroecto­ tumor
tumor growth
growth is is pronounced
pronounced and/ and/ or or refractory
refractory second-
second­

dermal
dermal margin margin of of thethe iris
iris and, and, forfor example,
example, to to deposit
deposit ary
ary glaucoma
glaucoma occurs, occurs, or or the
the tumor
tumor growsgrows over
over thethe pupil-
pupil­
on
on thethe lens
lens or or cause
cause retrocorneal
retrocorneal nodules. nodules. Fluorescein
Fluorescein lary
lary margin
margin and and affects
affects vision.
vision. 147, 150 Some
Sorne investigators
147· 150
investigators
angiographic
angiographic patterns p a tt e r n s may
may also also help
help differentiate
differentiate be- be­ advise
advise iridocyclectomy
iridocyclectomy for for peripheral
peripheral lesionslesions that
that either
either
tween
tween a a benign
benign and anda a malignant
malignant lesion.168-17°Benign
lesion.
168-170
Benign nevi nevi involve
involve the the chamber
chamber angle angle or or are
are associated
associated with with glau-
glau­
have
have a a filigree
filigree vascular
vascular network
network pattern pattern (early
( early filling,
filling, late
late coma,147,
coma, 147· 149 with
with the
149
the potential
potential visualvisual consequences
consequences and and

leaking),
leaking), or or theythey may may be be angiographically
angiographically silent, silent, while
while even
even mortality
mortality with with delayed
delayed tumortumor removal
removal dictating
dictating thisthis
malignant
malignant tumors tumors have have irregular
irregular and and indistinct
indistinct vascular
vascular course.
course. However,
However, since since upup toto 50%
5 0 % ofof patients
patients undergoing
undergoing
channels
channels that that fill fill later
later (i.e.,
( i . e . , in
in mpre
more than than 30 30 seconds).
s e co n d s ) . iridocyclectomy
iridocyclectomy retain retain nono useful
useful vision,
vision, some
sorne investigators
investigators
Although
Although these these features
features are are useful,
useful, they
they probably
probably should should have recommended
have recommended ultrasound-guided
ultrasound-guided needle needle biopsy
biopsy forfor
not
not be be used
used as as aa definitive
definitive or or decision-making
decision-making investiga-investiga­ cytologic
cytologic diagnosis
diagnosis before
before iridocyclectomy.142,
iridocyclectomy. 150 Because
142·
Because
150

tion
tion in in determining
determining malignancy.l7l
malignancy.
171
Several
Several otherother teststests it
it has
has been
been recognized
recognized that that thethe prognosis
prognosis of of iris
iris melano-
melano­
have
have beenbeen suggested
suggested but but notnot foundfound to to bebe useful.147,
useful. 149
147• 149
mas
mas isis good,
good, however,
however, therethere is is aa trend
trend toward
toward conservative
conservative

manageluent
management of of iris
iris lesions
lesions withwith local
local excision
excision (irido-
(irido­

Choroidal Melanomas
Choroidal Melanomas cyclectomy),
cyclectomy), with with follow-up
follow-up every
every few few months
months for for spindle
spindle

Choroidal
Choroidal melanoma
melanoma is
is diagnosed
diagnosed on
on the
the basis
basis of
of indirect
indirect B
B histology,
histology, and and enucleation
enucleation is is advised
advised onlyonly ifif epithelioid
epithelioid

ophthalmoscopy,
ophthalmoscopy, scleral
scleral transillumination,
transillumination, and
and ultraso-
ultraso- cells
cells are
are discovered
discovered on on biopsy,
biopsy, except
except in in the
the monocular
monocular
 CHAPTER 48: MASQUERADE
C H A P T E R 48: M A S Q U E R A D E SYNDROMES:
S Y N D R O M E S : MALIGNANCIES
M A LI G N A N C I E S lfD

patient. 152 Another

patient.
152
Another surgical modality for
surgical modality which smaller
for which smaller touch"
touch" technique
technique
191 and
and maintaining
maintaining normal
191
normal intraocular
intraocular

melanomas
melanomas of the ciliary
of the ciliary bodybody or or anterior
anterior choroids
choroids may may pressure
pressure during
during surgery.192, 193
surgery.l'":
193

be amenable
be amenable is partial lamellar
is partial lamellar sclerouvectomy.
sclerouvectomy.

The management of
The management of choroidal
choroidal tumors tumors is based on
is based on Prognosis
Prognosis
their size.
their size. AA major
major advance
advance in in thethe treatment
treatment of of choroidal
choroidal Most
Most melanocytic
melanocytic iris iris tumors
tumors behave
behave in in aa benign
benign fashionfashion

tumors is
tumors that of
is that of external
externa! beam beam radiation.
radiation. Pioneering
Pioneering (unlike
(unlike choroid
choroid and and ciliary
ciliary body
body melanomas
melanomas
166, 195) and
166
•and
195)

work on
work this modality
on this modality done done by by Gragoudas
Gragoudas and and associates
associates do
do notn o t metastasize.
m e t a s t a s i z e . Although
Although the the controversy
c o n t r o v e r s y as
as toto

of
of the
the Massachusetts
Massachusetts Eye Eye and and Ear Ear Infirmary,
Infirmary, among. among oth- oth­ whether
whether iris iris lesions
lesions are are inherently
inherently benign
benign or or not
not contin-
contin­

ers, has shown

ers, has shown encouraging
encouraging results results in in some
sorne laboratory
laboratory ues,
ues, most
most irisiris melanomas
melanomas have have a a good
good prognosis
prognosis unless unless

and
and animal
animal studies.
studies.
182 ,183 Advantages
Advantages of
1 8 2 • 183
this technique
of this technique are are metastatic
metastatic spreadspread
134 , 185 or
134• 185
or extraocular
extraocular extension
extension has has oc-oc­

that
that a a maximum
maximum density density of of ionization
ionization can can be be focused
focused curred.
curred.!"
188
onto
onto a a localized
localized volume,
volume, and and thusthus large-sized
large-sized tumorstumors and and In
In malignant
malignant melanomamelanoma of of the
the iris
iris and
and ciliary
ciliary body,
body,

tumors
tumors adjacent
adjacent to to critical
critica! structures
structures can can bebe treated.
treated. ThisThis overall mortality
overall mortality has has been been reported
reported at at 35%
3 5 % inin 5 5 years
years andand

modality
modality is being used
is being used in in certain
certain centerscenters in in thethe United
United 50%
5 0 % in
in 1010 years,196
years,
196
with
with thethe prognosis
prognosis depending
depending on on size
size

States
States and and other
other countries;
countries; the the major
major disadvantages
disadvantages are are (largest tumor
(largest tumor diameter
diameter in in contact
contact with
with sclera),
sclera), pigmenta-
pigmenta­

limited
limited availability
availability and and cost.cost. Concerns
Concerns about about its use in
its use in tion,
tion, cell
cell type,
type, scleral
scleral extension,
extension, mitotic
mitotic activity,
activity, location
location

humans
humans have have also been raised,
also been raised, with with aa study
study showing
showing the the of
of anterior
anterior margin
margin of of the
the tumor
tumor andand optic
optic nerve
nerve exten-exten­

use
use of of radiation
radiation prior prior to to enucleation
enucleation actually actually adversely
adversely sion,152
sion,
152
age
age at at enucleation,
enucleation, height height of of tumor,
tumor, and and thethe

affecting
affecting survival,184
survival,
184
hypothesized
hypothesized to to bebe the
the result
result of pre-
of pre­ integrity
integrity of of Bruch's
Bruch's membrane.
membrane.
153 The
153
The same
same studies
studies iden-
iden­

existing
existing metastases.
metastases. At present; therefore,
At present, therefore, the the most
most com-
com­ tify
tify a
a cutoff
cutoff size
size of of 10 1 0 mm
mm as as the
the most
most important
important marker, marker,

mon
mon modality
modality for for treating
treating medium-sized
medium-sized choroidal choroidal mela- mela­ aa size
size of
of 101 O mm
mm or or less
less having
having a a better
better prognosis
prognosis than than a a

nomas
n o m a s is is radiotherapy,
radiotherapy, employing employing either either radioactive
radioactive size of
size of more
more thanthan 10 1 O mm.
mm. TheThe five
five leading predictors of
leading predictors of

iodine
iodine (P25) (P
25)
or
or ruthenium
ruthenium (Ru
l06 plaques to
(Ru º ) plaques
1 6)
to the
the sclera
sclera survival
survival in in these
these studiesstudies werewere largest
largest diameter
diameter of of the
the

over
over thethe base
base ofof the
the tumor.
tumor. Transpupillary
Transpupillary thermotherapy
thermotherapy tumor,
tumor, epithelioid
epithelioid cells cells per
per high-power
high-power field,
field, invasion
invasion to to

is
is an
an emerging
emerging modality
modality for for thethe treatment
treatment of of small-
small- to to line
line of of transection,
transection, location location of of anterior
anterior margin
margin of of the
the

medium-sized
medium-sized tumors, tumors, pioneered
pioneered by by Shields
Shields and and associ-
associ­ tumor,
tumor, and and degree
degree of of pigmentation.
pigmentation.

ates.'?", 177 Large

ates. 176 177
Large tumors
tumors require
require enucleation
enucleation except except in in the
the

elderly,
elderly, unfit,
unfit, or or monocular
monocular patients. patients. For For medium-sized
medium-sized Condusions
Condusions

tumors,
tumors, distinguishing
distinguishing between between benign benign and and malignant
malignant Iris
Iris melanomas
melanomas and and choroidal
choroidal ciliary
ciliary melanomas
melanomas repre-
repre­

lesions
lesions becomes important. Gener~l
becomes important. Ccnerál health, health, age, age, and
and vi-vi­ sent
sen t two
two very
very different
different malignancies
malignancies of of the
the melanocytic
melanocytic

sion
sion in in the
the opposite
opposite eye eye alsoalso havehave to to be
be considered;
considered; a a stromal
stromal cells,
cells, which
which cancan masquerade
masquerade as as intraocular
intraocular in-
in­

course
course of of observation
observation for for growth
growth may may be justifiable in
be justifiable in flammation.
fl a m m a ti o n . Iris
Iris melanomas
m e l a n o m a s have
have a a typically
typically indolent
indolent

smaller
smaller tumorstumors in in older
older patients.
patients. In In small
small tumors,
tumors, differ-
differ­ course,
course, whereas
whereas choroidal
choroidal ciliary
ciliary melanomas
melanomas must be
must be

entiatingnevus
entiating nevus from from melanoma
melanoma is is important,
important, and and thethe distinguished
distinguished from from other
other similar
similar conditions,
conditions, asas the
the man-
man­

ratio
ratio of of height
height to to base
base diameter
diameter is is critical; pigmentation
critical; pigmentation agement
agemen t and and prognosis
prognosis depend
depend to to a
a very
very large
large extent
extent on
on

and
and secondary
secondary retinal retinal detachlnents
detachments also playaa role.
also play role. Dru-
Dru­ accurate
accurate diagnosis.
diagnosis.

senoid
s e n o i d appearance
a p p e a r a n c e indicates
i n d i c a t e s chronicity
chronicity and and thusthus maymay

point
point toward
toward a a benign,
benign, slow-growing
slow-growing tumor. tumor. In In most
most pa­pa- RETINOBLASTOMA

tients,
tients, a a period
period of of observation
observation is is adequate.
adequate. Medical
Medical evalu-evalu­

ation
ation in in patients
patients undergoing
undergoing enucleation enucleation is is important
important
Definition
D e fi n i t i o n

not
not only
only for for assessing
assessing the the general
general health health of of the patient
the patient
A
A retinoblastoma
retinoblastoma is
is a
a malignancy
malignancy arising
arising from
from the photo-
the photo­

receptor precursor cells

receptor precursor cells of
of the
the retina.
retina.
197, 198 It
It is
is the
the com-
197•
com­
198

but
but also
also in in looking
looking for for second
second malignancies
malignancies and and to rule
to rule

out
out metastases.
metastases.
monest
monest ocular
ocular tumor
tumor of
of childhood.
childhood.

History
History
Complications
Compllcations The
The first
first report
report of of retinoblastoma
retinoblastoma in in medical
medical or or ophthal-
ophthal­

Complications
Complications of partial resection
of partial resection of of iris
iris melanomas
melanomas are are mic
mic literature
literature comescomes from
from the the mid
mid 18th 18th century,
century, when
when

metastatic
metastatic spread,
spread, usually
usually through
through the the surgical
surgical wound
wound the
the case
case of of aa 3-year-old
3-year-old girl
girl with bilateral ocular
with bilateral tumors
ocular tumors

from
from glaucoma
glaucoma filtration
filtration procedures,185-190
procedures, and
and after
after surgi-
135-190
surgi­ was
was described.
described. William
William Hey,
Hey, in in 1805,
1 8 0 5 , introduced
introduced the the term
term
cal and
cal and accidental
accidental trauma.
trauma. The The complications
complications associated
associated fungus
fungus haematodes
haematodes to to describe
describe retinoblastomas
retinoblastomas and and other
other

with
with enucleation
enucleation include
include infection, bleeding, and
infection, bleeding, and extru-
extru­ highly
highly vascular,
vascular, fungating
fungating tumors,
tumors, but but itit was
was Wardrop,
Wardrop,

sion
sion or
or migration
migration of of the
the implant,
implant, as as well
well as
as the
the psychologi-
psychologi­ who,
who, in in his
his Observations
Observations on Fungus Haematodes
on Fungus Haematodes or Soft
ar So ft Can-
Can­

cal consequences
cal consequences of of loss
loss ofof one
one eye.
eye. This
This isis especially
especially cer,
cer, first
first brought
brought together
together the the scattered
scattered reports
reports andand de-
de­

severe for
severe for the
the asymptomatic
asymptomatic patient.
patient. Similarly,
Similarly, the
the compli-
compli­ scriptions
scriptions of of this
this tumor,
tumor, identified
identified its its retinal
retinal origin,
origin, and
and

cations
cations of
of radiation
radiation have
have been
been discussed
discussed elsewhere
elsewhere in in this
this distinguished
distinguished it it from
from "soft
"soft cancers"
cancers" in in general,
general, on on the
the

chapter.
chapter. Interestingly,
Interestingly, because
because of of the
the observation
observation thatthat few
few basis
basis ofof its
its occurring
occurring primarily
primarily in in children.
children.
199 199

patients
patients have
have metastases
metastases from from uveal
uveal melanoma
melanoma noted noted atat Virchow 20o coined the
Virchow ºº coined
2
the tenn
term retinal
retinal glioma,
glioma, which
which per­per-
the
the time
time of
of initial
initial presentation
presentation and and before
before enucleation,
enucleation, sisted
sisted in in the
the literature until it
literature until it was
was recognized
recognized that the
that the

some
sorne investigators
investigators have
have hypothesized
hypothesized that that enucleation
enucleation tumor
tumor arosearose from
from the
the neuroepithelial
neuroepithelial cells cells of the retina,
of the retina,
may
may potentiate
potentiate thethe spread
spread of of metastases.191-19'1
metastases.Pv l'" Most
Most sur-
sur­ when
when Verhoff,
Verhoff, of of the
the Massachusetts
Massachusetts Eye Eye and
and Ear
Ear Infir-
Infir­

geons
geons have
have emphasized
emphasized the the use
use of
of techniques
techniques to to minimize
minimize mary, named the
mary, named the tumor
tumor retinoblastoma.
retinoblastoma. Retinoblastomas
Retinoblastomas
the
the possible
possible spread
spread due due toto enucleation,
enucleation, suchsuch asas the
the "no
"no have been
have been studied
studied extensively
extensively as as a part of
a part molecular
of molecular
mi CHAPTER
CHAPTER 48:
48: MASQUERADE
MASQUERADE SYNDROMES:
SYNDROMES: v
IM A U G N A N ....
DJlo1IdL.D'l..:lID"llA"'l-R"II C In::.::»
ES

genetics,
genetics, and
and they
they have
have been
been vital
vital to
to our
our understanding
understanding indeed
indeed be
be the
the most
most COlnmon,
common, inin developing
developing countries. 209
counrries.s'"

of
of how
how genes
genes cause
cause cancer.
cancer. Patients
Patients may
may also
also present
present with
with pinealoblastoma,210,
pinealoblastoma.t'? 211 aa
211

retinoblastoma
retinoblastoma inin the
the pineal
pineal body,
body, although
although these
these gener-
gener­

Epidemiology
Epidemiology ally
ally occur
occur at
at a
a stage
stage when
when patients
patients have
have already
already been
been

The
The incidence
incidence of of retinoblastoma
retinoblastoma is is 11 inin 20,000
20,000 infants
infants diagnosed
diagnosed with
with retinoblastoma.
retinoblastoma.

and
and children.
children. The
The vast
vast majority
majority of of retinoblastomas
retinoblastomas pres- pres­

ent
ent in
in children
children under
under 3 3 years
years of
of age-the
age-the tumor tumor rarely
rarely
Pathophysiology,
Pathophysiology, Pathology,
Pathology, and
presents in
presents in children over 5
children over 5 years.
201 Around 40%
years."?' Around 40% of of reti-
reti­

noblastomas
noblastomas are are familial-that
familial-that is, is, the
the mutation
mutation in in the
the
Immunology
lmmunology

retinoblastoma
retinoblastoma genegene is is a
a germ-line
germ-line Inutation
mutation that that isis trans-
trans­
The
The genetics
genetics of of retinoblastoma
retinoblastoma have have been been of of great
great inter-inter­

Initted
mitted from
from the
the parents,
parents, and·and 60%
60% areare sporadic;
sporadic; however,
however,
est
est to
to molecular
molecular biologists
biologists studying studying cancer. cancer. HumanHuman cells cells

not
not all
all familial
familia! cases
cases have
have a positive fanlily
a positive family history.
history. Seventy
Seventy
are
are known
known to to carry
carry two two copies
copies of of the
the retinoblastoma
retinoblastoma gene gene

(Rb),, a
(Rb) a cancer
cancer suppressor
suppressor or or proto-oncogene,
proto-oncogene, located located
percent of
percent of these
these tumors
tumors are are unilateral
unilateral and and 30% 30% bilateral,
bilateral,

with
with familial
familial cases typically presenting
cases typically presenting bilaterally.
bilaterally.
on
on chromosome
chromosome 13q14. 1 3 q l 4 . According
According to to Kn.udson's
Knudson's two-hit two-hit

The
T h e familial
familia! cases
c a s e s are
are generally
generally diagnosed
d i a g n o s e d earlier,
earlier,
hypothesis, which
hypothesis, which has has since
since been been substantiated
substantiated by by consid-
consid­

many
many by by screening
screening examinations
examinations in in infancy;
infancy; bilateral
bilateral cases
cases
erable
erable experimental
experimental evidence, evidence, both both normal
normal allelesalleles of of the
the

Rb locus
Rb locus mustmust be be inactivated
inactivated for for retinoblastoma
retinoblastoma to to de-de­
are
are diagnosed
diagnosed at ataan
n average
average age of 15
age of 1 5 months
months and and unilat-
unilat­

eral
eral cases
cases at
at 24
24 months.
months.F"
202 velop.
velop. InIn familial
familial cases,
cases, children
children are are bornborn withwith one one nor-nor­

mal
mal andand oneone defective
defective copy copy of of thethe Rb Rb gene.
gene. The The second
second

Clinical
C l i n i c a l Characteristics
Characterlstics
copy
copy is is lost
lost through
through some sorne form form of of somatic
somatic mutationmutation

The
The two two mostmost common
common modes modes of of presentation
presentation are are leuko-
leuko­
(point
(point mutation,
mutation, interstitial
interstitial deletiondeletion of of 13q14,
l 3q 14, or or even
even

koria
koria and and strabismus,203,
strabismus, º
2 3•
204 highlighting
204
highlighting the the needneed for for aa
cOlnplete
complete loss loss of of chromosome
chromosome 13). 1 3 ) . Loss
Loss of of both
both copiescopies

dilated
dilated fundus fundus examination
examination in in allall patients
patients with with strabis-
strabis­
gives
gives rise
rise toto retinoblastoma.
retinoblastoma. Since Since the the first
first Inutation
mutation is is aa

Inus.
mus. A A lessless common
common presentation
presentation is is asas intraocular
intraocular in- in­
germ-line
germ-line mutation
mutation inherited
inherited from from an an affected
affected parent,parent, it it

flammation
flammation 205;
205 ; other
other uncommon
uncommon presentations presentations include include
is
is present
present in in all
all cells
cells of of the
the body,
body, whereas
whereas the the second
second

secondary
secondary glaucoma, glaucoma, proptosis,
proptosis, and and a a pinealoblastoma.
pinealoblastoma.
mutation
mutation (the (the second
second hit) hit) occurs
occurs in in a a retinal
retinal precursor
precursor

Because
Because distant distant metastases
metastases tend tend to to occur
occur late,late, mostmost pa- pa­
cell
cell whose
whose progeny
progeny then then give give riserise to to thethe retinoblastoma;
retinoblastoma;

tients
tients present present with with local
local signs
signs before
before distant
distant Inetastasis.
metastasis.
this
this mutation
mutation is is thus
thus present
present only only in in cells
cells ofof thethe tumor
tumor

Intraocular
Intraocular inflammationinflammation may may be be true
true inflamlnation
inflammation
itself.
itself. In
In sporadic
sporadic cases,cases, both both normal
normal Rb Rb genes
genes are are lost
lost byby

(i.e.,
( i . e . , an
an inflammatory
inflammatory response response to to necrosis
necrosis of of thethe tumor)
tumor)
somatic
somatic mutation
mutation in in one one of of the
the retinoblasts.
retinoblasts. Thus Thus the the

or
or only only simulated
simulated inflammation
inflammation as as tumor
tumor cellscells enter
enter thethe
mutations
mutations are are present
present only only in in thethe progeny
progeny of of this
this reti-
reti­

anterior
anterior chamber chamber and and simulate
simulate anterioranterior uveitis.
uveitis. Retino-
Retino­
noblast, which
noblast, which then then formform the the tumor.
tumor.

blastoma
blastoma can can easily
easily be be confused
confused with with granulomatous
granulomatous uve- uve­
Patients
Patients with with familial
familia! retinoblastoma,
retinoblastoma, who who have have a a mu-
mu­

itis of
itis of almost
almost any any cause,
cause, including
including tuberculous
tuberculous and and syphi-
syphi­
tant
tant copy
copy of of the
the gene
gene in in all
all cells
cells of of thethe body,
body, are are alsoalso atat

litic.
litic. 206·
206 , 207 Weizenblatt
207 207 reports aa case
Weizenblatt''" reports case of of anan 8-year-old
8-year-old
aa greatly
greatly increased
increased risk risk of of developing
developing osteosarcomaosteosarcoma and and

boy,
boy, initially
initially presenting
presenting with with unilateral
unilateral decreased
decreased vision, vision,
some
sorne other
other soft soft tissue
tissue sarcomas.
sarcomas. Interestingly,
Interestingly, inactivation
inactivation

ciliary injection,
ciliary injection, balledballed and and strand-like
strand-like vitreous
vitreous opacities,
opacities,
of
of the Rb locus
the Rb locus has has been
been observed
observed in in several
several other
other tumors,
tumors,

and
and a a gray
gray focus
focus in in the
the fundus,
fundus, but but with
with no no retinal
retinal mass.mass.
including
including adenocarcinoma
adenocarcinoma of of the
the breast,
breast, smallsmall cell cell carci-
carci­

The
The patient patient was was initially
initially diagnosed
diagnosed and and managed
managed as as hav-
hav­
noma
noma of of the
the lung,
lung, and and bladder
bladder cancer. cancer. Because
Because of of the
the

ing
ing uveitis,
uveitis, but but on on recurrence
recurrence of of symptoms,
symptoms, he he was
was con-
con­
familial
familial nature
nature of of retinoblastoma,
r e t i n o b l a s t o m a , risk
risk assessment
a s s e s s m e n t be-
be­

sidered
sidered to to have
have endophthalmitis
endophthalmitis and and was was evaluated
evaluated for for
comes
comes important
important for for falnily
family members.
members. This This willwill be be dis-
dis­

possible
possible tuberculous,tuberculous, syphilitic,
syphilitic, brucellaI',
brucellar, tularemic,
tularemic, and and
cussed
cussed later.
later.

toxoplasmic
toxoplasmic etiologies. etiologies. The The diagnosis
diagnosis of of retinoblastOlna
retinoblastoma
Spread
Spread of of the
the retinoblastoma
retinoblastoma may may be be direct
direct (into (into the the

was made
was made only only after
after the the patient's
patient's death death more more than than a a
orbital
orbital tissues
tissues fromfrom the the globe),
g l o b e ) , via
via thethe optic
optic nervenerve into into

year
year later. later.
the
the CSF,
CSF, andand hematogenously
hematogenously to to the
the bonebone marrow.
marrow. Dis- Dis­

205 reports aa case

Ellsworth º reports
Ellsworth 2 5
case of of left
left esotropia
esotropia at at birth
birth andand
tant
tant metastases
metastases occur occur late late in in thethe course
course of of thethe disease
disease

aa typical
typical picturepicture of of granulomatous
granulomatous uveitis uveitis withwith vitreous
vitreous
(Fig. 48-4).
(Fig. 48-4).

haze
haze that that made made examination
examination of of thethe fundus
fundus impossible,
impossible,

which
which later later proved
proved to to bebe a a retinoblastoma
retinoblastoma with with massive
massive Diagnosis
Diagnosis

involvement
involvement of of the
the choroid.
choroid. And And Stafford
Stafford and and colleagues
colleagues Because
Because a a retinoblastoma
retinoblastoma is is the
the most
most common
common intraocu-
intraocu­

report
report a a case
case series
series in in which
which nearlynearly 40% 40% of
of patients
patients lar
lar malignancy
malignancy of of childhood,
childhood, anyany patient
patient with
with the the pre-
pre­

with
with retinoblastoma
retinoblastoma had had been been initially
initially misdiagnosed
misdiagnosed with with senting
senting signs
signs ofof leukokoria,
leukokoria, strabismus,
strabismus, or or uveitis
uveitis must must

uveitis.r'" Because
uveitis. 208 Because delay delay in in the
the diagnosis
diagnosis of of this
this tumor
tumor is is have
have thisthis condition
condition ruled
ruled out.
out. The
The differential
differential diagnosis
diagnosis

associated
associated with with spread
spread and and a a high
high mortality,
mortality, it it is
is essential
essential of
of leukokoria
leukokoria includes
includes persistent
persistent hyperplastic
hyperplastic primary
primary vit- vit­

to
to consider
consider and and exclude
exclude retinoblastoma
retinoblastoma in in any any major
major reous, posterior
remIS, posterior cataract,
cataract, retrolental
retrolental fibroplasia,
fibroplasia, retino- retino­

disease
disease in in the
the eye eye of of a a child
child thatthat precludes
precludes a a view
view of of blastoma,
blastoma, coloboma
coloboma of of choroid
choroid or or optic
optic disc,
disc, and and uve- uve­

the
the fundus.
fundus. itis. 212 As
itis. As mentioned,
212 mentioned, around
around 40%40% ofof misdiagnosed
misdiagnosed cases cases

Among
A m o n g the the uncommon
u n c o m m o n presentations,
p r e s e n t a ti o n s , secondary
secondary of
of retinoblastOlna
retinoblastoma may may initially
initially be
be diagnosed
diagnosed as as uveitis.
uveitis.?"
208
angle-closure
angle-closure glaucoma glaucoma occurs occurs as as a a result
result of of mass
mass effect
effect Other
Other rarerare intraocular
intraocular tumors
tumors of of childhood
childhood (e.g.,
( e . g . , medul-
medul­

closing
closing the the anterior
anterior angle.angle. Proptosis,
Proptosis, causedcaused by by growth
growth of of 10epitheliOlna,
loepithelioma, and and possibly
possibly optic
optic gliomas)
gliomas) maymay also also be
be

the
the tumor tumor into into the the orbit,
orbit, is is aa rrare
a r e presentation
presentation in in devel-
devel­ diagnosed
diagnosed as as retinoblastoma.
retinoblastoma. These
These can
can generally
generally be be ex-
ex­

oped
oped countries,
countries, but but it it isis extremely
extremely common, common, and and maymay cluded
cluded by by aa thorough
thorough clinical
clinical history
history and
and examination,
examination,

s
 CHAPTER 48:
CHAPTER 4 8 : MASQUERADE
M A S Q U E R A D E SYNDROMES:
S Y N D R O M E S : MALIGNANCIES
M A LI G N A N C I E S m:D

FIGURE
F I G U R E 48-4.
48-4. Flexner-Wintersteiner rosettes, which
Flexner-Wintersteiner rosettes, which
are
are characteristic
characteristic of retinoblastoma. (Courtesy
of retinoblastoma. (Courtesy of
of

Thadeus
Thadeus P. P. Dqja,
Dryja, MD.)
MD.) (See
(See color
color insert.)
insert.)

although
although some patients may
sorne patients may p present
resenta a difficult
difficult diagnostic
diagnostic Blood samples from affected individuals are used to iden-
Blood samples from affected individuals are used to iden­

problem.
problem. tify the
tify the germ-line mutation in
germ-line mutation the Rb
in the Rb gene.
gene. Searching
Searching for for

In pediatric patients
In pediatric patients suspected
suspected of this malignancy
of this malignancy or or this mutation
this mutation in the parents
in the parents and and siblings
siblings of the patient
of the patient
presenting with
presenting uveitis, aa family
with uveitis, history is
family history vital, followed
is vital, followed helps assess
helps the risk
assess the risk of retinoblastoma in
of retinoblastoma the siblings
in the siblings and
and

by aa complete
by complete eye eye examination,
examination, including
including a visual acuity
a visual acuity future
future siblings
siblings of,'the patient. In
ofthe patient. nonfamilial cases,
In nonfamilial the
cases, the

and
and dilated
dilated fundus
fundus examination.
examination. The The fundus
fundus examination
examination germ-line mutations are
germ-line mutations not present.
are not present. However,
However, even even in
in

is
is usually
usually carried
carried out under general
out under general anesthesia,
anesthesia, with with care-
care­ familial
familial cases
cases it
it is
is sometimes
sometimes not not possible
possible to to identify the
identify the

ful documentation
ful documentation of of the
the size
size al'id
añd location
location of the tumor
of the tmllor germ-line mutation by
germ-line mutation by direct methods, and
direct methods, restriction
and restriction

on
on a a large
large fundus
fundus drawing, which is
drawing, which is essential
essential for for follow-
follow­ fragment
fragment length polYITIorphisms (RFLP)
length polymorphisms (RFLP) or or other DNA
other DNA

up and
up planning radiation.
and planning radiation. Bone marrow aspiration
Bon.e marrow aspiration and and polymorphism analysis
polymorphism analysis of two or
of two more family
or more members
family members

biopsy, and
biopsy, and a a lumbar puncture for
lumbar puncture for cytocentrifuge
cytocentrifuge exami- exami­ affected
affected byby the
the disease
disease maymay be be necessary.
necessary. If the patient
If the patient is
is

nation,
nation, may may also also be be performed
performed under under the the same
same anesthe-
anesthe­ the only
the only individual
individual affected
affected by by the
the disease, these RFLPs
disease, these RFLPs
sia,
sia, although
although the usefulness of
the usefulness of such methods has
such methods has recently
recently cannot
cannot bebe used,
used, but
but risk
risk is predicted by
is predicted by aa study
study of whether
ofwhether

been questioned.
been questioned.
213213 the disease
the was unifocal
disease was unifocal or multifocal (which
or multifocal (which includes
includes

Ancillary
Ancillary measures
measures includein.elude CT CT ofof the
the orbit
orbit and head 214
and head
214
bilateral retinoblastoma,
bilateral retinoblastoma, multifocal
multifocal retinoblastoma,
retinoblastoma, uni­ uni-
which
which may may lead lead to to a a diagnosis
diagnosis of pinealoblastoma215 but
of pinealoblastoma
215
but focal retinoblastoma with
focal retinoblastoma with aa related
related primary
primary in in the
the CNS,
CNS,
is
is ofof limited
limited value value in in evaluating
evaluating optic nerve involvement,
optic nerve involvement, and unifocal retinoblastoma
and unifocal retinoblastoma with with aa subsequent osteosar-
subsequent osteosar­

because
because spread spread to to the
the optic
optic nerve
nerve is is infiltrative
infiltrative and and does
<loes coma)
coma) andand a genetic analysis
a genetic analysis ofof cells
cells obtained
obtained from from the
the
not
not generally
generally enlargeenlarge the the nerve.
nerve. It It may,
may, however,
however, distin-
distin­ tumor. The
tumor. The risk
risk of developing retinoblastoma
of developing retinoblastoma in in offspring
offspring
guish
guish between
between an an invading
invading tumortumor and and oneone merely
merely imping-
imping­ and
and siblings
siblings of the patient
of the patient is is then
then calculated
calculated and and forms
forms
ing
ing on on thethe nerve.
nerve. Occasionally, retinoblastoma calcifica-
Occasionally, retinoblastoma calcifica­ the basis
the basis on which these
on which these at-risk
at-risk individuals
individuals are are followed,
followed,
tions
t i o n s may
may be be visible
visible on the CT
on the CT scans e a n and
and may may h help
elp if necessary,
if necessary, with
with examination
examination under under anesthesia.
anesthesia.
distinguish retinoblastoma from
distinguish retinoblastoma non-neoplastic condi-
from non-neoplastic condi­

tions. 216
tions.i":, 217 A
217
bone scan
A bon.e sean maymay identify
identify a bone metastasis,
a bon.e metastasis, Treatment
Treatrnent

although
although it it is not used
is not used regularly
regularly in in aspllptomatic
asymptomatic pa­ pa- Ellsworth, in
Ellsworth, in 1969, observed that
1 9 6 9 , observed that in
in the
the treatment
treatment of of
tients.
tients.
21s Reports
218 Reports show show that that MRI
MRI maymay helphelp estimate
estimate differ-
differ­ retinoblastoma, "life
retinoblastoma, "life isis gambled
gambled for for sight,
sight, "205
205
" and this
and this
entiation
entiation in in retinoblastomas.
retinoblastomas.
219219 Lactate
Lactate dehydrogenase
dehydrogenase holds true
holds true even today with
even today with thethe targets
targets for
for treatment
treatment being
being
(LDH)
(LDH) levels levels in in the
the aqueous
aqueous humor humor may may also
also be be very
very the complete
the control of
complete control of malignancy
malignancy andand the
the preservation
preservation
helpful
helpful in in a a difficult
difficult differential
differential diagnosis.
220 Elevated
diagnosis. º Elevated
22
of useful vision.
of useful vision.
total
total LDH LDH levelslevels in in the
the aqueous humor are
aqueous humor very sensitive
are very sensitive The most
The most commonly
commonly used used treatment
treatment in in patients
patients with
with
and
and fairly
fairly specific
specific for retinoblastoma, although
for retinoblastoma, although they they must
must good prognostic
good prognostic factors
factors (Reese-Ellsworth criteria la,
(Reese-Ellsworth criteria la, lb,
Ib,
be interpreted
be interpreted with with caution
caution in patients with
in patients with glaucoma
glaucoma or or lIa,
Ila, and
and lIb;
Ilb; Table
Table 48-1)48-1) 205 is
205
is external beam radiation.
external beam radiation.
large
large numbers
numbers of of histiocytes
histiocytes and neutrophils in
and neutrophils the eye,
in the eye, Because of
Because the numerous
of the numerous side side effects
effects of radiation on
of radiation on the
the
and
and theythey may may also
also be be elevated
elevated in in conditions
conditions such such as as Coats'
Coats' normal tissue
normal tissue of of thethe eye,
eye, a balance must
a balance must be be achieved
achieved
disease.
disease. LDH LDH isoenzYITIe
isoenzyme patternspatterns in in the
the aqueous
aqueous humor, humor, between providing
between providing sufficiently high and
sufficiently high and extensive
extensive radia­
radia-
and
and the the ratio
ratio of of aqueous
aqueous humor humor to to serum
serum LDH LDH are are of
of tion for
tion for a realistic chance
a realistic chance of of eradicating
eradicating thethe cancer,
cancer, andand
doubtful
doubtful value value and probably not
and probably not useful
useful in in establishing
establishing minimizing the
minimizing the radiation
radiation exposure
exposure of of normal
normal tissue.
tissue. Ex­
Ex-
the
the diagnosis
diagnosis of of retinoblastoma.221-234
retinoblastoma.P'<-" ternal beam
ternal beam radiation
radiation therapy
therapy (EBRT),
(EBRT), either
either through
through a a
Blood
Blood specimens
specimens must must be be obtained
obtained from from the the patient,
patient, Weiss 226 approach
Weiss
226
approach of of aa two-field
two-field plan
plan ((a classic split-field,
a classic split-field,

parents, and
parents, and siblings
siblings for for DNA
DNA analysis
analysis for risk assessment.
for risk assessment. an ipsilateral temporal
an ipsilateral temporal field,field, and
anda a more
more lightly
lightly weighted
weighted
lfml CHAPTER 48: MASQUERADE
CHAPTER 48: MASQUERADE SYNDROMES:
S Y N D R O M E S : MALIGNANCIES
M A LI G N A N C I E S

TABLE 4 8 - 1 . THE
TABLE 48-1. T H E REESE-ELLSWORTH
REESE-ELLSWORTH CRITERIA
CRITERIA to
to treat
treat thethe eye eye with
with radiation
radiation may may be be made
made if if the
the out-
out­

Ia
la Solitary
Solitary tumor
tumor less
less than
than 4 4 dd
dd oror behind
behind the the equator
equator
come
come of of treatment
treatment with with radiotherapy
radiotherapy seems seems otherwise
otherwise

bb Multiple
Multiple tumors,
tumors, none
none larger
larger than
than 44 dd,
dd, all
all at
at or
or behind
behind the
the
favorable
favorable in in terms
terms of of visual
visual rehabilitation).
rehabilitation).

equator
equator Following
Following enucleation,
enucleation, pathologic
pathologic examination
examination of of the
the
Ila
IIa Solitary
Solitary tumor
tumor 4-10
4-10 dd,
dd, at
at or
or behind
behind thethe equator
equator obtained
obtained specimen
specimen is is conducted
conducted to to identify
identify spread
spread into into
bb Multiple
Multiple tumors,
tumors, 4-10
4-1 O dd,
dd, atat or
or behind
behind the the equator
the
the orbit
orbit or or globe,
globe, which
which may may require
require combinedcombined radiation
equator
radiation
IlIa
IIIa Any
Any lesion
lesion anterior
anterior to
to the
the equator
equator
232 Tu-
b Solitary
b Solitary tumor
tumor larger
larger than
than 101 O dd
dd behind
behind the the equator
equator
and
and chemotherapy,
chemotherapy, or or very
very rarely
rarely an an exenteration.
exenteration.
232
Tu­

IVa
IVa Multiple
Multiple tumors,
tumors, some
sorne larger
larger than
than 10
1 O dd
dd mor
mor cells
cells areare obtained
obtained and and used
used for for DNADNA analysis
analysis to to help
help

b Any
b Any lesion
lesion extending
extending anteriorly
anteriorly toto the
the ora
ora serrata
serrata identify
identify the the mutations
mutations causing causing the the tumor.
tumor. At At the
the timetime of of
Va
Va Massive
Massive tumor
tumor involving
involving over
over half
half the
the retina
retina
enucleation,
enucleation, a a long
long segment
segment of of the
the optic
optic nerve
nerve should
should be be
b Vitreous
b Vitreous seeding
seeding
obtained
obtained in in anan effort
effort to to ensure
ensure removal
removal of of any
any optic
optic nerve
nerve

dd,
dd, disc
clise diameter.
diameter.
invaded
invaded by by tumor,
tumor, and and the the nerve
nerve should
should be be examined
examined for for
From
From Ellsworth
Ellsworth RM:
RM: The
The practical
practical management
management of
of retinoblastoma. Trans Am
retinoblastoma. Trans Am evidence
evidence of of tumor
tumor invasion.
invasion.
Ophthalmol
Ophthalmol SocSoc 1969;67:463-534,
1969;67:463-534, with
with permission.
permission.
Photocoagulation
Photocoagulation and and cryotherapy
cryotherapy are are other
other modal-modal­

ities
ities ofof treatment.
treatment. These These are are used
used primarily
primarily when when the the

tumors
tumors are are small,
small, fewfew in in number,
number, and and remote
remote from from the the
anterior
anterior field),
fi e l d ) , or
or through
through Schipper's227,
Schipper's 228 or
227• 228
or Harnett's229
Harnett's
229
disc
clise and
and macula.
230
macula. º·, 233, 234 They
23 233• 234
They are are used used as as second-line
second-line
contact
contact lens
lens treatment
treatment (with (with a a temporal
temporal split-field
split-field photonphoton treatment
treatment for for recurrences
recurrences after after EBRT,
EBRT, with with photocoagula-
photocoagula­
approach),
a p p ro a c h ) , provides
provides more m o r e exten~ive
exterisive radiation;
r a d i a t i o n ; cobalt
cobalt tion
tion used
used for for more
more posterior
posterior and and cryotherapy
cryotherapy for for more
more
plaque approaches
plaque approaches lead lead toto more
more limited
limited radiation
radiation expo- expo­ anteriorly
anteriorly located
located tumors.
tumors. However,
However, these these techniques
techniques are are
sure
sure but
but are
are unsuitable
unsuitable for for patients
patients with
with significant
significant vitre- vitre­ not
not very
very successful
successful when when viableviable tumor
tumor masses masses have have broken
broken
ous
ous seeding,
seeding, two two or or more
more tumors,
tumors, large
large (>10
( > 1 0 mm) mm) tu- tu­ from
from the the mainmain tumor
tumor mass mass during
during EBRT, EBRT, settled
settled along along
mors,
m o r s , or
or tumors
tumors near n e a r or
or onon the
the macula,
m a c u l a , since
since thethe the
the vitreous
vitreous base, base, andand continued
continued to to grow.
grow.
potential
potential forfor newnew tumor
tumor development
development or or incomplete
incomplete radi- radi­ Control
Control in in both
both these
these modalities
modalities (in (in contrast
contrast to to control
control
ation
ation of of existing
existing tumor tumor exists.
exists. in
in radiotherapy)
radiotherapy) is is defined
defined as as complete
complete disappearance
disappearance of of
Follow-up of
Follow-up of patients
patients undergoing
undergoing radiotherapy
radiotherapy is is im-
im­ the
the tumor,
tumor, with with formation
formation of of a a flat
flat scar.
scar.
235 This
235
This mightmight
portant
portant to to observe
observe and and document
document regression
regression of of disease.
disease. take
take a a few
few weeks
weeks to to evolve,
evolve, and and both
both cryopexy
cryopexy and and photo-
photo­
This
This inCludes
includes examination
examination of of the
the patient
patient toward
toward the the end
end coagulation
coagulation can can be be repeated
repeated if if aa response
response does <loes not
not occur
occur
of
of radiotherapy,
radiotherapy, and and a a repeat
repeat examination
examination under under anesthe-
anesthe­ with
with thethe initial
initial treatment.
treatment. Photocoagulation
Photocoagulation involves involves us- us­
sia at 6
sia at 6 weeks
weeks after after radiotherapy,
radiotherapy, with with documentation
documentation on on ing
ing a a laser
laser to to put
put a a double
double row row of of burns
burns around
around each each
large
large retinal
retinal drawings
drawings at at each
each visit.
visit. Successful
Successful local local con-
con­ tumor.
tumor. Cryotherapy,
Cryotherapy, performed performed trans-sclerally,
trans-sclerally, involves involves
trol
trol following
following radiotherapy
radiotherapy is is defined
defined as as a a failure
failure of of the
the three
three to to four
four freeze-thaw
freeze-thaw cycles. cycles.
tumor
tumor to to enlarge.
enlarge. However,
However, therethere are
are aa number
number of of differ-
differ­ Photoactive
Photoactive dyes dyes havehave beenbeen used used in in conjunction
conjunction with with
ent
ent patterns
patterns of of response
response that that the
the tumor
tumor can can show:
show: laser
laser or or electromagnetic
electromagnetic energy energy in in treatment,
treatment, althoughalthough

clinical
clinical experience
experience with with thisthis is
is still
still limited.
limited. The The technique
technique
Type
Type 1:
1 : Conversion
Conversion of of tumor
tumor to to a
a lumpy,
lumpy, calcified
c a lc i fi e d
involves
involves absorption
absorption of of photoactive
photoactive dyes dyes by by the
the tumor
tumor mass mass
mass-the
mass-the "cottage
"cottage cheese"
cheese" appearance
appearance
and
and therefore
therefore increased
increased vulnerability
vulnerability to to treatment
treatment with with
Type 2:
Type 2: Change
Change from
from solid,
solid, pink,
pink, or
or opaque
opaque andand vascular,
vascular,
laser,
laser, 236 ultraviolet
236
ultraviolet light,light, or or visible
visible light.light. 237
237

to
to translucent,
translucent, gray,
gray, and
and less
less vascular,
vascular, the
the "fish-flesh"
"fish-flesh"
Long-term
Long-term follow-up follow-up of of patients
patients is is planned
planned after after thethe
appearance
appearance
initial
initial therapy.
therapy. Examination
Examination under under anesthesia
anesthesia is is carried
carried
Type 3: A
Type 3: A combination
combination of of types
types 11 and
and 22

Type out
out every
every 3 3 months
months for for 4 4 years,
years, every every 6 6 months
months for for
Type 4:
4: Total
Total loss
loss of
of tumor,
tumor, retina,
retina, and
and choroid,
choroid, leaving
leaving
another 2
another 2 years,
years, and and then then annually
annually for for an additional 2
an additional 2
bare
bare sclera230
sel era
230

years,
years, when
when most most children
children are are oldold enoughenough to to tolerate
tolerate

Larger
Larger tumors tumors show show types
types 1 or 3
1 or 3 and
and smaller
smaller onesones annual
annual peripheral
peripheral retinal retinal examinations
examinations without without anesthe-
anesthe­

types 2
types or 3
2 or 3 patterns.
patterns. Very
Very small
small tumors
tumors may may showshow a a type
type sia.
sia. Regular
Regular ophthalmic
ophthalmic screening screening appropriate
appropriate for for ageage isis

44 pattern.
pattern. LargerLarger tumors,
tumors, however,
however, tendtend notnot to to change,
change, also conducted.
also conducted. These These children
children must must also also be
be screened
screened for for

or
or to
to shrink
shrink only only slowly
slowly over
over time.
time. AsAs mentioned,
mentioned, failurefailure secondary
secondary nonocular
nonocular tumors tumors associated
associated with with retinoblas-
retinoblas­

to
to increase
increase in in size
size represents
represents local local success
success of of radiother-
radiother­ toma.
toma.

apy.
apy. Siblings
Siblings in in whom
whom the the riskrisk of
of thethe hereditary
hereditary retinoblas-
retinoblas­

The
The second
second modality
modality of of treatment
treatment is is enucleation.
enucleation. Enu- Enu­ toma
toma genegene cannot
cannot be be excluded
excluded must must also also bebe followed
followed up up

cleation
cleation should
should be be considered
considered in in all
all eyes
eyes where
where there
there isis regularly.
regularly. This This usually
usually takes takes the the form form of of examinations
examinations

no
no chance
chance of of preserving
preserving usefuluseful vision.
vision.
205 Indications
205
Indications in- in­ under
under anesthesia
anesthesia every every 3 3 months
months up up to to 4 4 years
years of of age,
age,

clude
elude unfavorable
unfavorable Reese-Ellsworth
Reese-Ellsworth (see (see Table
Table 48_1)205
48-1)
205
cri-
cri­ and
and less
less frequently
frequently thereafter.
thereafter. The The frequency
frequency of of examina-
examina­

teria, including
teria, including tumors tumors anterior
anterior to to the
the ora
ora serrata,
serrata, espe-
espe­ tions
tions cancan be be altered
altered in in those
those with
with low low risk
risk (1 (1 %% to to 5%),
5%),

ciallywith
cially with anterior anterior segment
s e g m e n t invasion,
invasion , totaltotal retinal
retinal and
and eyeeye examinations
examinations without without anesthesia
anesthesia may may be be used
used in in

detachment,
detachment, and and a a posterior
posterior segment
segment fullfull of
of tumor.
tumor. Rela-
Rela­ those
those with
with extremely
extremely low low risk
risk «0.1
( < 0 . 1 %).
%) .

tive indications
tive indications include include invasion
invasion of of optic
optic nerve
nerve by by tu-
tu­

mor 231 (it may

mor'"! (it may be be helpful
helpful to to obtain
obtain a a CT
CT scan
sean to to decide
decide Prognosis
Prognosis
whether
whether the the tumor
tumor is is invading
invading or or merely
merely impinging
impinging on on Overall,
Overall, in
in countries
countries where
where adequate
adequate medical
medical care
care facili-
facili­

the
the nerve),
n e r v e } , viable-looking
viable-looking vitreous
vitreous seeds
seeds that
that areare poorly
poorly ties for
ties for early
early detection
detection and
and treatment
treatment of
of this
this disease
disease are
are

responsive
responsive to to radiation
radiation (as
( as it
it is
is difficult
difficult to to assess
assess the
the available,
available, the
the prognosis
prognosis of
of retinoblastoma
retinoblastoma isis good.238-242
good.
238-242

viability
viability of of vitreous
vitreous seeds
seeds by by examination
examination alone,alone, attempts
attempts More
More than
than 85%
8 5 % of
of children
children in
in developed
developed countries
countries have
have
 C H A P T E R 48:
CHAPTER 48: MASQUERADE
M A S Q U E RA D E SYN[JIRC)MIES:
S Y N D R O M E S : MALIGNANCIES
MAUGNANCIES IIO

long-term
long-term survival survival following
following retinoblastoma.
retinoblastoma.T", 243 In
202 243 In de-de­ is
is the
the commonest
commonest initial initial cause
cause of of vision
vision loss
loss in in children
children

veloping
veloping countries
countries where where such such facilities
facilities are are notnot readily
readily treated
treated with with twotwo or or more
more full full courses
courses of of EBRT
EBRT to to the
the

available,
available, the the survival
survival rate rate isis poor.
poor.
209
209
entire
entire retina.
201 Plaque approaches
retina.'?' Plaque approaches can can also
also cause
cause vascular
vascular

Several
Several prognostic
prognostic indicators indicators for for retinoblastoma
retinoblastoma have have damage,
d a m a g e , hemorrhage,
h e m o r r h a g e , and
and subsequent
s u b s e q u e n t vitreous
v i t r e o u s opac-
opac­

been
been studied.
studied. The The Reese-Ellsworth
Reese-Ellsworth criteria criteria (see (see Table
Table 48-48-
ity.216,217
ity.216, 217

1),
1 ) , the
the present
present criteria criteria of of suitability
suitability for for radiation
radiation using using Effects
Effects of of radiation
radiation on on growing
growing tissues
tissues include
include hypopla-hypopla­

tumor
tumor controlcontrol and and vision
vision preservation
preservation as as end
end points,
points, sia
sia ofof temporal
temporal bone, bon.e, above
above a a threshold
threshold level level of of 2000
2000 toto

divide
divide the the tumor tumor into into different
different prognostic
prognostic categories.categories. 3500
3500 cGy.cGy. These
These changes,
changes, however,
however, if if symmetrical,
symmetrical, are are not
not

Studies
Studies also also show show that that local
local spread
spread into into the the orbital
orbital tissues
tissues cosmetically
cosmetically disfiguring.
disfiguring. This This complication
complication is is markedly
markedly

and
and thethe optic
optic nerve
2022· 232, 244 decreases survival,
nerve2 º ,232, 244 decreases survival, although
although decreased
decreased in in plaque
plaque therapy.
therapy. Similarly,
Similarly, failure
failure of of eruption
eruption

local
local spread
spread is is usually
usually still still quite
quite controllable;
controllable; survival survival of of of
of molar
molar teeth
teeth hashas been
been reported.
reported.

patients
patients with with optic optic nerve
nerve spreadspread depends depends also also on on the
the Second
Second tumor tumor formation,
formation, as as discussed
discussed previously,
previously, has has

extent
extent of of posterior
posterior involvement
involvement of of thethe nerve.
nerve. Massive
Massive classically
classically been been attributed
attributed to to radiotherapy,
radiotherapy, but but therethere is is

choroidal
choroidal involvement
involvement may may also also havehave some sorne prognostic
prognostic evidence
evidence that that the
the risk
risk ofof second
second tumors
tumors in in patients
patients with with

significance. 245 Although retrobulbar

significance.245 Although retrobulbar spread spread and and spread
spread hereditary
hereditary retinoblastoma
retinoblastoma is is extremely
extremely high high regardless
regardless of of

outside
outside the the orbit orbit was· was · traditionally
traditionally considered
considered fatal, fatal, the
the radiation
radiation use. use. These
These tumors
tumors are are believed
believed to to occur
occur whenwhen

use
use ofof combined
combined chemotherapy chemotherapy has has resulted
resulted in in long-term
long-term changes
changes at at both
both thethe 13q14
1 3 q l 4 loci
loci eliminate
eliminate production
production of of

survival
survival and and apparent apparent cure cure in in some
sorne patients
patients with with bone
bone the
the tumor
tumor suppressor
suppressor gene; gene; these
these tumors
tumors also also follow
follow a a

marrow
marrow spread.239-242
s p r e a d . 2 3 9 - 2 4 2 Pinealoblastomas,
P i n e a l o b l a s t o m a s , onon thethe other
other two-hit pattern,
two-hit pattern, withwith thethe first
first hit
hit in in extraocular
extraocular tissues tissues

hand,
hand, have have a a very
very poor
poor prognosis,
prognosis, being being uniformly
uniformly fa- fa­ being
being the the germ-line
germ-line mutation,
mutation, and and the the second
second hit hit being
being
tal. 210, 211
tal. 210, 211
caused
caused by by some
sorne other
other mutagen,
mutagen, which which couldcould be be radiation.
radiation.

However,
However, even even if if the
the retinoblastoma
retinoblastoma is is survived,
survived, indi-indi­ Both
Both alleles
alleles being
being inactivated
inactivated in in aa nonocular
non.ocular tissue tissue gives
gives

viduals
viduals with with the the 13q14
1 3 q l 4 locus
locus abnormalities
abnormalities in in thethe germ-
germ­ rise to
rise to aa tumor
tumor of of that
that tissue.
tissue. The
The rolerole ofof radiation
radiation in in this
this

cell
cell line
line (i.e.,
( i . e . , in
in hereditary
hereditary retinoblastoma)
retinoblastoma) have have an an in-
in­ complication
complication may may possibly
possibly be be addressed
addressed in in thethe future
future byby

creased
creased risk risk of of other
other malignancies,
malignancies, the the commonest
commonest being being more
more effective
effective neoadjuvant
neoadjuvant chemotherapy
chemotherapy followed followed by by

osteosarcoma,
osteosarcoma, followed followed by by malignant
malignant melanoma. melanoma. Other Other more
more locallocal approaches
approaches including
including radiation.
radiation.
238 , 242 How-
238· 242
How­

malignancies
malignancies with with a a higher
higher risk risk in in these
these patients
patients include
in.elude ever, the
ever, the only
only hope
hope for for the
the elimination
elimination of of such
such tumors
tumors

soft
soft tissue
tissue sarcomas,
sarcomas, skin skin cancers,
cancers, leukemias,
leukemias, lymphomas,
lymphomas, lies
lies inin gene
gene therapy
therapy that
that cancan reverse
reverse effects
effects of of thethe germ-
germ­

and
and brain
brain tumors-2%
tumors-2% to to 5%
5 % of of these
these children
children developdevelop line
line mutation.
mutation.

tumors
tumors of of the pineal region.246,~~52
the pineal Because
Because about about 67%
52
region.24 5,f.2 67%

of
of these
these tumors
tumors are are in in thethe radiation
radiation field,246field,246 they they have
have Conclusion
C o n cl u s i o n
traditionally
traditionally been been considered
considered radiation radiation induced. induced. How- How­ Retinoblastoma
Retinoblastoma is is a
a childhood
childhood malignancy
malignancy that
that can
can mas-
mas­

ever, these
ever, these tumors tumors also also occuroccur in in patients
patients who who have have notnot querade
querade as as uveitis.
uveitis. Diagnosis
Diagnosis isis important
important because
because the
the

received
received radiation
radiation therapy,246
therapy,246 and and it it has
has been
been shownshown thatthat tumor
tumor is is curable
curable ifif treated
treated early
early and
and must
must be be ruled
ruled out
out

although
although the the irradiated
irradiated group group initiate
initiate secondsecond tumor tumor de- de­ in
in all
all children
children with
with uveitis.
uveitis. Not
Not only
only is
is it
it important
important toto

velopment
velopment approximately
approximately 5 5 years
years earlier
earlier than than the the nonirra-
nonirra­ treat
treat the
the index
index case
case but
but also
also to
to determine
determine thethe familial
familia!

diated
diated group,
group, the the frequency
frequency of of second
second tumor tumor develop-
develop­ nature
nature of of the
the disease
disease and
and to
to counsel
counsel and
and follow-up
follow-up rela-
rela­

ment
ment is is approximately
approximately equal equal with with or or without
without radiation,
radiation, tives.
tives.

and
and furthermore
furthermore that that the the ultimate
ultimate total total riskrisk ofof tumors
tumors in in

patients
patients with with hereditary
hereditary retinoblastoma
retinoblastoma is is extremely
extremely high high METASTASIS
METASTASIS
regardless
regardless of of radiation
radiation therapy.242
therapy.242 The The extentextent of of mortality
mortality

from
from the the second
second tumors tumors is is controversial,
controversial, with with various
various Definition
D e fi n i t i o n

series
series reporting
reporting ranges
ranges from from 59% 5 9 % of of bilateral
bilateral retinoblas-
retinoblas­ Metastatic
Metastatic disease
disease is is the
the commonest
commonest malignancy
malignancy affecting
affecting

toma
toma patients
patients dead dead by by 35 35 years
years afterafter diagnosis,
diagnosis, to to others
others the
the eye,255
eye,
255
and
and its its incidence
incidence is is growing
growing as
as patients
patients with
with

with
with onlyonly 4% 4% after after 30 30 years.
2'18-251 This
years.2'18-251 This disparity
disparity may may be be systemic malignancies
systemic malignancies survive survive longer.
longer. Metastases
Metastases to to the
the

the
the result
result of of selection
selection biases biases in in the
the patient
patient population.
population. eye
eye were
were firstfirst reported
reported by by Horner
Horner in in 1864,256
1864,256 andand they
they

were
were initially
initially believed
believed to to be
be uncommon.
uncommon.
257 , 258 But
257· 258
But in
in the
the

Complications
C o m p l ic a t i o n s late
late 1 9 O O s , it carne to be recognized that metastatic malig-
1900s, it came to be recognized that metastatic malig­

Radiotherapy
Radiotherapy can can potentially
potentially be be associated
associated with with a a large
large nancies
nancies werewere more more common
common than than previously
previously thought,
thought,

variety
variety of
of complications.
complications. TheseThese include
include cataract
cataract forma-
forma­ with
with incidences
inciden.ces among among various
various groups
groups of
of cancer
cancer patients
patients

tion,
tion, retinal
retinal vasculitis,
vasculitis, changes
changes in in irradiated
irradiated tissue,
tissue, and
and ranging
ranging fromfrom 4.7%4 . 7 % to
to 27%.257-259
27%.
257-259

possibly,
possibly, second
second malignancies.
malignancies.

Cataract
Cataract formation
formation is is ilnportant
important because,
because, in in aa child,
child, Epidemiology
Epidemiology
this
this almost
almost always
always leads
leads toto amblyopia.
amblyopia.
253
253
Temporal
Temporal fieldsfields Although
Although ocular
ocular metastasis
metastasis is
is rare
rare for
for most
most cancers,
cancers, its
its

seem
seem to to protect
protect against
against cataract
cataract formation,201
formation,
201
but
but the
the incidence
inciden.ce is
is increasing
increasing asas the
the survival
survival time
time forfor cancers
cancers

newer
newer lateral
lateral field
field approaches,
approaches, where
where there
there is is an
an intersec-
intersec­ increases
in.creases and
and asas metastatic
metastatic manifestations
manifestations becomebecome moremore

tion
tion ofof the
the lens
lens and
and thethe anterior
anterior field
field edge,
edge, lead
lead toto common
common and and surveillance
surveillance for
for them
them becomes
becomes more more vigi-
vigi­

increased
increased cataract
cataract production.
production.
254 However,
254
However, the the technique
technique lant.
lant. Choroidal
Choroidal metastasis
metastasis in
in patients
patients dying
dying of of systemic
systemic

developed
developed by by Weiss
Weiss and
and colleagues,226
colleagues,
226
Inentioned
mentioned pre- pre­ malignancies
malignancies range
range from
from 5%
5 % to
to 27%;
2 7 % ; this
this broad
broad reported
reported

viously,
viously, minimizes
minimizes the the risk
risk when
when properly
properly conducted.
conducted. range
range probably
probably reflects
reflects the
the variety
variety ofof patients
patients seen
seen in
in any
any

Retinal
Retinal vasculitis
vasculitis isis another,
another, dose-dependent,
dose-dependent, and and po-
po­ particular
particular setting.
setting. In
In breast
breast cancer
cancer patients
patients with
with no
no ocular
ocular

tentially
tentially visually
visually devastating
devastating consequence
consequence of of radiation.
radiation. It It symptoms,
symptoms, forfor example,
example, the
the incidence
incidence is is 9.2%,
9 . 2 % , whereas
whereas itit
lifI;J CHAPTER 48: MASQUERADE
M A S Q U E R. A D E SYNDROMES:
. C H A P T E R 48: S Y N D R O M E S : MALIGNANCIES
MAUGNANCIES

is
is 27%
2 7 % in in those
those withwith symptoms,260
symptoms,"? and and autopsyautopsy studies
studies

report
report even higher incidences
even higher incidences (37% ( 3 7 % in patients dying
in patients dying of of

breast cancer,255
breast cancer, 9.3%
9 . 3 % in
255
patients dying
in patients dying of of all types of
all types of

cancers
cancers
261 ), probably
261),
probably reflecting
reflecting the the addition
addition of of cases
cases withwith
subclinical
subclinical ocular metastasis.
ocular metastasis.

The most common

The most common primary primary cancerscancers for for ocular metasta-
ocular metasta­

sis
sis are
are the breast,262-266 the
the breast, the lungs,127,
262-266
lungs,
127•
263, 264, 267 and
263, 264,
and "un-
267
"un­

known," in
known," that order.
in that order. However,
However, breast breast cancer metasta-
cancer metasta­

sizes
sizes to to thethe eye eye late
late in in itsits course,
course, so so thatthat it it is usually
is usually

clinically evident
clinically evident elsewhere,
elsewhere, either either in in the the breast
breast itself,
itself,

or
or asas lung
lung or or disseminated metastases 260 before
disseminated metastases'"" before ocularocular

sYluptoms
symptoms arise. arise. The malignancies with
The malignancies with the the highest
highest inci­ inci-
dence
dence of of ocular presentation preceding
ocular presentation preceding extraocular extraocular de­ de-
tection are
tection are lung
lung and renal cell
and renal cell carcinoma.
carcinoma. The incidence
The incidence

of
of lung
lung cancer metastatic to
cancer metastatic to the
the eyeeye is is increasing
increasing as as thethe
incidence
incidence of this cancer
of this cancer increases,
increases, and and lung metastases
lung metastases
FIGURE 48-5. Metastases
are now the
are now the commonest
commonest malignancies malignancies of of the iris. 268 , 269
the iris. 268, 269 F I G U R E 48-5. Metastases toto the
the choroid. Note the
choroid. Note the multiple
multiple lesions
lesions
and
and irregular
irregular outline.
outline. Choroidal metastases are
Choroidal metastases typically multiple,
are typically multiple, have
have
Metastases from
Metastases from cancers
cancers of the kidney
of the kidney and prostate and
and prostate and
an
an irregular
irregular outline,
outline, are yellow-gray to
are yellow-gray to pink-white
pink-white in
in color with edema-
color with edema­
cutaneous
cutaneous melanoma melanoma are are not uncoluluon. 127, 262, 263, 267, 270º
not unconunon.!": 262, 263, 267, 27
tous and
tous and detached
detached overlying retina, are
overlying retina, are generally
generally several
several disc
disc diameters
diameters

Metastases from
Metastases from adenocystic cancer;Merkel's male
adenocystic cancervMerkels male breast
breast in
in size,
size, and may have
and may have overlying
overlying clumps
clumps of pigment. (See
of pigment. (See color
color insert.)
insert.)

cancer,
c a n c e r , and
a n d choriocarcinoma
c h o r i o c a r c i n o m a have have also also b been
een r re-
e­

ported.271-277
ported. 271-277

Clinical
Clinical series series on on thethe incidence
incidence of of ocular luetastases
ocular metastases
rhage, increased
rhage, increased intraocular pressure, and
intraocular pressure, and anterior
anterior and and
from
from different
different primaryprimary malignancies
malignancies· tend tend to to select
select for for posterior uveitis.
posterior uveitis.
the less
the less aggressive malignancies (e.g.,
aggressive malignancies breast), when
( e . g . , breast), when the the Posterior uveitis
Posterior uveitis in metastatic malignant
in metastatic malignant masquerade
masquerade
metastases have
metastases have· had
had timetime to to grow
grow and and manif manifest est asas ocular
ocular
has been
has been reported
reported to to p
present
resenta ass clumps
clumps of pigmented or
of pigmented or
sYJ-llptoms,
symptoms, whereas whereas autopsy autopsy studies studies have have comparatively
comparatively
nonpigmented cells
nonpigmented cells on vitreous strands,
on vitreous which may
strands, which may par­par-
higher frequencies
higher frequencies of the more
of the more aggressive malignancies,
aggressive malignancies,
tially obscure
tially obscure the the view
view of the retina
of the retina and which are
and which are discov-
discov­
when death
when death occurs occurs beforebefore the the ocular
ocular disease becomes
disease becomes
ered
ered toto be
be refractory
refractory to to steroid treatment.
steroid treatment.
clinically manifest. Interestingly,
clinically manifest. Interestingly, some malignancies are
sorne malignancies are
An anterior
An anterior segment presentation is
segment presentation less common,
is less common, but but
also
also associated
associated with with aa higher
higher incidence
incidence of primary choroi-
of primary choroi­
patients may
patients may have
have sYJ-llptoms
symptoms of blurred vision,
of blurred vision, red
red eye,
eye,
dal
dal cancers:
cancers: The relationship between
The relationship between breast breast cancer
cancer and and
photophobia, pain,
photophobia, pain, and and (occasionally)
( occasionally) spontaneous
spontaneous hy­ hy-
primary choroidal
primary c h o ro i d a l m n1.elanoma
e l a n o rn a has has b been
e e n wellwell docu-
docu­
278 This, then, phema. Patients
phema. Patients are reported to
are reported to have
have iritis
iritis or
or anterior
anterior
mented.
rnented.v" This, then, indicates
indicates the need to to differentiate
glaucoma28o (in
the need differentiate
uveitis (in
uveitis nearly half),
(in nearly half), secondary
secondary glaucoma
280
(in around
around
primary choroidal
primary choroidal cancerscancers from metastases in
from metastases in a patient
a patient
two thirds),
two thirds), and
anda a mass
mass lesion
lesion of the iris
of the iris (60%),279
(60%),
279
which
which
with
with a a systemic
systemic malignancy.
malignancy.
is most commonly
is most commonly an inferiorly situated
an inferiorly gray-white or
situated gray-white or
The
The most most frequent
frequent sites sites forfor ocular metastasis are
ocular metastasis are thethe pink nodule,
pink nodule, although
although infiltrative
infiltrative lesions
lesions may may alsoalso bebe
posterior choroid,263,
posterior choroid, 264 the·
the orbit,
263, 264
orbit, the the iris,iris, andand thethe ciliary
ciliary
present. Typical
present. presentations include
Typical presentations include mildmild nongranulo­
nongranulo-
body,255,
body,
255,
264, 279 in
264,
in that
279
that order.
order. Metastases
Metas tases to to thethe retina
retina are are
263 , 267 matous anterior
matous uveitis with
anterior uveitis with associated increase in
associated increase in intra­
intra-
rare
rare andand occuroccur in in less than 1
less than 1%% ofof cases.
263, 267
cases.
ocular pressure, refractory
ocular pressure, refractory to to steroid treatment, or
steroid treatment, recur'"'
or recur­

rent after
rent the treatment
after the treatment is is stopped.
stopped.
281 Anterior
281
Anterior segment
segment
Clinical
C li n ic a l Characteristics
Characteristics
presentations are
presentations typically associated
are typically with tumor
associated with tumor location
location
The
The patient
patient may may be be aSYJ-llptomatic.
asymptomatic. When When symptoms
symptoms are are
in the anterior
in the anterior segment
segment of the eye,262
of the eye,
262
and gonioscopy is
and gonioscopy is
present,
present, posterior
posterior segment segment sYJ-llptoms
symptoms such such as as decreased
decreased
an
an obviously important diagnostic
obviously important diagnostic step step in in such cases.
such cases.
visual
visual acuity,
acuity, floaters,
floaters, and and field
field defects
defects areare thethe ones
ones most
most
263 Metamorphopsia, Despite careful
Despite careful examination,
examination, however, however, no no visible
visible lesion
lesion
often
often reported.
reported. M e t a m o r p h o p s i a , diplopia,
263
d i p l o p í a , red
red eye,
eye,
may be
may be detected
detected in in the
the eye. Denslow and
eye. Denslow and Rielar,
Kielar, forfor
ptosis,
p t o s i s , anisocoria,
a n i s o c o r i a , and
and exophthalmos
e x o p h t h a l m o s are
are otherother p pre-
re­
263 Pain example, reported aa case
example, reported case in in which
which no no obvious
obvious lesions
lesions
senting
senting signs. signs. Pain may
263
may also
also occur,
occur, and and this
this along with
along with
were identified
were identified in in thethe eye,
eye, nor nor could
could aa primary
primary malig­
malig-
unexplained
unexplained retinal retinal detachment,
detachment, glaucoma, neovasculari-
glaucoma, neovasculari­
nancy be
nancy be found,
found, although
although bone bone metastasis
metastasis occurred
occurred laterlater
zation,
zation, and and uveitis
uveitis should
should alertalert thethe clinician
clinician to to the possi-
disease. 281
the possi­
267 in the course
in the course of the disease.
of the
281

bility of
bility of metastatic
metastatic cancer. cancer.
267

On
On examination,
examination, visual visual acuity
acuity is is frequently
frequently decreased,
decreased,

but
but itit may
may improve
improve through through refraction.
260 Slit-lamp exami-
refraction."? Slit-lamp exami­ Pathophysiology, Pathology,
Pathophysiology, Pathology, and
and

nation
nation and and dilated
dilated funduscopic
funduscopic examination
examination may may disclose
disclose Immunology
lmmunology
serous
serous retinalretinal detachment
263
detachment-'", 264 with with a
264
a flat
flat elevation
elevation of of Spread
Spread of tumors to
of tumors to the
the eye
eye is
is via
via the
the hematogenous
hematogenous
the
the retina
retina and and choroid.
choroid. Choroidal
Choroidal metastases
metastases typicallytypically route, most
route, most commonly
commonly through
through thethe pulmonary
pulmonary circula­
circula-
have
have an an irregular
irregular outline,
outline, are are yellow-gray
yellow-gray to pink-white in
to pink-white in tion and
tion and then
then vía
via the
the carotids
carotids into
into the
the ciliary
ciliary arteries,
arteries,
color
color with with edematous
edematous and and detached
detached overlying
overlying retina, retina, are
are and thence
and thence toto the
the choroid.
choroid. This
This explains
explains thethe high
high inci­
inci-
generally
generally several several disc clise diameters
diameters in in size,
size, andand luay have
may have dence of
dence of lung
lung metastasis
metastasis (up
(up toto 85%) in people
8 5 % ) in people with
with
overlying
overlying clumps clumps of pigment. They
of pigment. They are are frequently
frequently multi­ multi- metastatic ocular
metastatic ocular malignancy.
malignancy.127 TheThe origin
origin of
127
of the
the left
left
ple and
ple bilatera12 60 (Fig.
and bilateral"? (Fig. 48-5).
4 8 - 5 ) . Disc
Disc edema
edema may may also be
also be common carotid
common carotid artery
artery directly
directly from
from thethe aorta
aorta has
has been
been
present. Other
present. possible findings
Other possible findings include vitreous hemor-
include vitreous heluor- suggested as
suggested as an
an explanation
explanation forfor the
the preponderance
preponderance of of
 CHAPTER 48: MASQUERADE
C H A P T E R 48: SYNDROMES:
MASQUERADE S Y N D R O M E S : MALIGNANCIES
MAUGNANCIES

lesions
lesions in in left
left eyes reported by
eyes reported by some
some=":255 , 259, 262, 264, 265, 267,
259, 262, 264, 255, 267,
misdiagnosis),
mi whereas metastatic
s diagnosis ), whereas metastatic tumors
tumors ccan give a
an give a wide
wide
282-285 but
282-285
but not
not others,
others, and the distribution
and the distribution of of ciliary
ciliary arter-
arter­ variety of signals.292-294 MRI
variety of signals. MRI is
292-294
is also
also clearl
clearly helpful
y he lpful foforr the
the
ies
ies isis sometimes
sometimes used used toto explain why these
explain why these lesions
lesions are are evaluation
evaluation of the brain
of the brain for lesions.. 293
metastatic lesions
for metastatic
293

more
m o r e frequent
fr e q u e n t at the p
at the posterior
osterior p pole
o l e and temporally,
and temporally, For iris
For iris lesions,
lesions, anterior chamber tap
anterior chamber tap and
and cyt cytology
ology

where
where there
there is is aa greater
greater density
density of these blood
of these blood vessels.
vessels. have been
have been suggested
suggested for diagnosis in
for diagnosis in diffic
difficult cases. 286 , 295
ult cases.
286, 295

Some
Sorne tumor
tumor cells may, however,
cells may, however, bypass
bypass the the lungs
lungs and and Cytologic
Cytologic features
features of the cells
of the obtained by
cells obtained by this
this metho
method d

reach
reach the the eyeeye via
via Batson's vertebral plexus
Batson's vertebral plexus of veins, or
of veins, or may h
may help
elp distinguish between metastatic
distinguish between metastatic andand melanotic
melanotic
they
they maymay simply
simply be be too
too small
small toto be
be filtered
filtered out out by by the
the nodules and
nodules and also provide clues
also provide clues aboabout the origin
ut the origin of of the
the
pulmonary
pulmonary blood blood vessels.
vessels. This has b
This has been
e é n suggested
suggested as as an
an primary tumor
primary tumor in the case
in the case of iris metas
of iris metastases with
tases wi th anan occ
occult
ult

explanation
explanation for for the
the absence
absence of of lung metastasis of
lung metastasis the
of the primary. Direct
primary. Direct ciliary body
ciliary bod lesion biopsy
y lesion biopsy hashas also
also been
been
primary cancer
primary cancer in in about
about 15%
1 5 % of
of cases.
cases. reported and
reported and found
found toto be
be diagnostic
diagnostic in in aa case
case of
of carcinoid
carcinoid
tumor metastatic
tumor metastatic toto the iris. 296
the iris. 296

Diagnosis
Diagnosis At the
At the same time, if
same time, if metastases
metastases are are suspected
suspected in in the
the
The
The major major differential
differential diagnosisdiagnosis in these patients
in these patients is that
is that absence
absence of of a known
a kn primary, the
own primary, the patient
patient is
is also
also evaluated
evaluated
of primary uveal
of primary uveal melanoma.
melanoma. The The distinction
distinction is is ilnportant
important for the p
for the primary tumor. E
rimary tumor. Elevated
levated carcinoembryonic
carcinoembryonic anti­ anti-
as
as thethe twotwo conditions
conditions are are managed
managed differently
differently and and carrycarry gen
gen (CEA)
( CEA) levels
levels also
also suggest metastases when
suggest metastases when aa primary
primary
very
very different prognoses. Other
different prognoses. Other majormajor differential
differential diagno- diagno­ tumor has
tumor has not
not been
been identified,281,
identified.t'": 297 b
but
ut CEA
CEA is is aa nonspe
297
nonspe-­
ses
ses of of choroidal
choroidal metastases
metastases are rhegmatogenous retinal
are rhegmatogenous retinal cific marker of
cific marker malignancy. CEA
of malignancy. CEA and galnma-glutamyl-
and gamma -glutamyl­

detachment
detachment and and choroidal
choroidal granulomas.
granulomas. Differentiation
Differentiation of of transpeptidase
transpeptidase levels may
levels ma be used
y be used adjunctively
adjunctively to to distin-
distin­

metastatic
metastatic ocular ocular malignancy
malignancy from primary uveal
fróm primary uveal mela­mela- guish
guish metastasis
metastasis from
from amelanotic melanomas. 298
amelan o tic melanomas.
298

noma
noma is is based
based on on thethe characteristic
characteristic clinical clinical findings
findings of of

flat,
flat, infiltrative
infiltrative choroidal
choroidal lesions lesions with with largelarge overlying
overlying reti­ reti- Treatment
Treatment

nal
nal detachments
d e t a c h m e n t s in in metastatic
m e t a s t a ti c disease, which may
d i s e a s e , which may b bee By
By far
far the
the most
most common
common treatmenttreatment in patients wi
in patients with
th ocular
ocular

multifocal
multifocal and biiateraP60 There
and bilateral."? There is is a history of
a history malig-
of malig­
metastatic
metastatic disease
disease is radiotherapy. The
is radiotherapy. patients have
The patients have metameta-­
nancy
nancy in in many
many cases,cases, and and this this is is clearly
clearly very very helpfulhelpful static
static (and
(and therefore
therefore often often end-stage)
end- stage) disease,
disease, so radia-
so radi a­

in
in the the clinical
clinical differentiation
differentiation process. process. DiffuseDiffuse choroidal
choroidal
tion
tion isis used
used for palliation and
for palliation and to to improve
improve vision vision and and

infiltration
infiltration and vitreous seeding
and vitreous seeding with with no no obvious
obvious choroi- choroi­
quality
quality of of life;
life; most
most stLldies report around
studies report around a a 90%
9 0 % success
success

dal
dal massmass has has also been described
also been described in malignant skin
in malignant Inela-
skin mela­
rate
rate with
with radiation
radiation in in achieving
achieving stabilization
stabilization of of vivision
sion andand

286 ,287 Primary improved

improved qualityquality of of life.
260 , 299-305
260, 299-3
º
5
Radiation
Radiation is is also used
noma
noma metastatic
metastatic to to the
the eye. eye.
286, 287
Prilnary uveal uveal melano­
melano- life. also used

mas,
mas, by by contrast,
contrast, are are characteristically
characteristicallv described described as bulky
as bulky
when
when thethe lesions
lesions are are causing
causing retinal
retinal detachment,
detachment, or when
or when

growths
growths with with a a collar-button
collar-button appearance,
appearance, as they rupture
as they rupture they
they are
are rapidly
rapidly enlarging
enlarging despitedespite the the fact that the
fact that the patient
patient
through
through the the Bruch's
Bruch's membranemembrane and and are are associated
associated with with is
is on
on systemic
systemic chemotherapy.260
chemotherapy.
260

small retinal
small retinal detachments,
detachments, although although this this is not always
is not always the the Enucleation
Enucleation is is indicated
indicated when when metastases
metastases are are suspected
suspecte d

case.
case. They They are are generally unilateral, single
generally unilateral, single lesions
lesions and and
but
but primary
primary uveal uveal melanoma
melanoma cannot cannot be be excluded
excluded (al- ( al­

have
have only only a a weak
weak association
association with with other malignancies
other malignancies
though
though this this isis rare
rare and and eye-saving
eye-saving measures
measures such such as nee-­
as nee

dle
dle biopsy
biopsy of of choroidal
choroidal lesionslesions has been reported 3(6 in
reported º ); in
3 6);

(e.g.,
( e . g . , breast
breast cancer).
c a n c e r ) . Serial
Serial funduscopic
funduscopic examinations examinations
has been

usually
usually show show a a more
more rapidrapid growth
growth in in the
the case
case of of Inetasta-
metasta­
the
the case
case of of low-grade
low-grade malignancies
malignancies and and solitary metastasis
solitary metastasis

sis. Amelanotic
sis. Amelanotic uveal uveal melanomas
melanomas may present aa difficult
may present difficult
to
to the
the eye,
eye, when
when excision
ex ci sion of of thethe primary
primary malignancy
malignancy and and

the
the solitary
solitary metastasis
metastasis may may effect
effect a a cure
cure
264 ,307, 308 (this
264, 307, 308
this may
may
differential
differential diagnosticdiagnostic challenge challenge and, and, while
while additional
additional
(

studies
studies may may provide
provide clues, clues, the the clinical
clinical examination
examination in- in­
occur
occur with
with carcinoid
carcinoid tumors tumors or, or, occasionally,
occasionally, with with renal
renal

cell
cell carcinomas
3(9 ); and
and for
for a a blind
blind andand intractably painful
cluding
cl uding indirectindirect ophthalmoscopy
o p h t h a l m o s co p y usually provides the
usually provides the
carcinomas="): intractably painf ul

most
most reliable
reliable meansmeans of of distinguishing
distinguishing these these tumors
tumors from from
eye
eye when
when enucleation
enucleation may may improve
improve the the quality
quality oflife.
of life.

choroidal
choroidal metastases.metastases.
154 The
154
The iris,iris, in in metastatic
metastatic disease, disease,
Rarely,
Rarely, in in anterior
anterior uvealuveal disease,
disease, locallocal excision
excision is useful
is use ful

may
may show show prominent
prominent vascularity.
vascularity.
as
as an
an eye-preserving
eye-preserving measure. measure. When When visionvision is not bein
is not being g

Choroidal
Choroidal metastases
metastases exhibit exhibit early early blockage
blockage of of the
the cho-
cho­
threatened,
threatened, systemic
systemic therapy
therapy and and observation
observation are usually
are usuall y
sufficient.277,
sufficient."?" 310
310

roidal
roidal blood blood flow flow on on fluorescein
fluorescein angiography,
angiography, with with latelate

staining
staining of of and
and leakage·
leakage from from these these vessels.
vessels. Fluorescein
Fluorescein
Complications
C o m p l ic a t i o n s
angiography
angiography of of iris
iris metastases
metastases shows shows extensive
extensive leakage leakage
Complications
Complications of of radiotherapy
radiotherapy include include madarosis, radia-
madarosis, radi a­
of
of the the irisiris vessels.
vessels.
288 Ultrasonography
288
Ultrasonography shows prominent
shows prominent
tion-induced
tion-induced cataract, cataract, keratoconjunctivitis,
keratoconjunctivitis, and radiation
and radiation
acoustic
acoustic brightness
brightness with with moderate
moderate to to high
high internal
internal re- re­
retinopathy.
retinopathy. These These were
were discussed
discussed in in some
so rn e detail
detail in the
in the
flectivity, compared
flectivity, compared to to the the characteristic
characteristic findings findings of of cho-
cho­
earlier
e a r li e r section
s e c t i o n on
on retinoblastoma.
r e ti n o b l a s t o m a . However, many p
H owever, many pa-
a­
roidal
ro idal melanomas
melanomas on on ultrasonography,
u lt rasonography, described pre-­
d e s c r i b e d pre
tients
tients do do not
not survive
survive long
long enough
enough to to experience
experience thethe full
full
viously
viously in in this
this chapter.
chapter. In I n the
the case c a s e ofof effusions
effusions and and
force
force of of these
these side side effects.
effects.
detachments,
detachments, the the metastatic
metastatic lesions lesions can can b bee difficult
difficult to to
see,
see , and
and therefore
therefore ultrasonography
ultrasonography can can be be extremely
extremely valu- valu­ Prognosis
Prognosis
able
able in in helping
helping to to establish
establish the the diagnosis.
diagnosis. º
28 280 The
The prognosis
prognosis for
for patients
patients with
with metastatic
metastatic ocular
ocular disease
disease

MRI
MRI can can alsoalso be be useful
useful in in differentiating
differen tiating metastases metastases is poor
is poor (overall
( overall survival
survival of
of 66 to
to 12
1 2 months
months
262 ), as
as Inetasta-
262),
metasta­

from
from uveal uveal melanomas.289-291
melanomas.
239-291
Uveal
Uveal melanomas
melanomas have have beenbeen sis represents
sis represents disseminated
disseminated cancer
cancer but
but differs
differs for
for various
various

described
desc ri bed as as having
having a a characteristic
chara c teristic MRI MRI appearance
appearance wi withth primary
primary tumors
tumors and
and with
with location
location within
within thethe eye.
eye. Long-
Long­

aa high
high signalsignal intensity
intensity resulting
resulting from from short short T1 relaxation
T I relaxation term
term survival
survival of
of patients
patients with
with solitary
solitary carcinoid
carcinoid tumor tumor

times,
times , (although
( although this this is is not
not always
always the the casecase and and clinical
clinical metastatic
metastatic toto the
the eye
eye has
has been
been reported.
re p orted .
307, 308, 311 Breast
307,
Breast
308, 311

correlation
correlation of of the
the MRIMRI findings
findings is is always
always essential
essential to to avoid
avoid cancer tends to metastasize late in its course,
cancer tends to metastasi z e late in its course, whereas whereas
m) CHAPTER
CHAPTER 48:
4 8 : MASQUERADE
MASQUERADE SYNDROMES:
S Y N D R O M E S : MALIGNANCIES
MAUGNANCIES

lung
lung cancer
cancer metastasizes
metastasizes early.
early. Cutaneous
Cutaneous melanOlnas
melanomas Epidemiology
Epidemiology
also
also tend
tend to
to metastasize
metastasize to
to the
the eye
eye later,
later, and
and in
in association
association CAR
CAR seems
seems to to be
be equally
equally common
common in in men
men andand women;
w ome n;
with widespread
with widespread metastasis,286,
metastasis, 287, 311-313 and
and therefore
therefore they
286' 287, 311-313
they in
in aa summary
summary of of 28
28 patients
patients with
with CAR,318
CAR, 16
1 6 were
were men
318
me n
have
have one
one of
of the
the worst
worst prognoses.
prognoses. and 12
and 1 2 were
were women.
women. The The patients
patients are
are generally
generally older
older

adults,
adults, thethe same
same summary
summary reporting
reporting an an age
age range
range be-
be­
Conclusion
Conclusión
tween 37
tween and 76
37 and 76 years, with 22
years, with of 28
22 of 28 patients being 60
patients being 60
Metastatic
Metastatic malignancy
malignancy to to the
the eye
eye can
can masquerade
masquerade as as uve-
uve­
years
years or or older.
older. Many
Many patients
patients with
with CAR
CAR areare slllokers,
s m okers,
itis, and
itis, and the
the uveitic
uveitic masquerade
masquerade may may bebe the
the first
first pre-
pre­
and
and this
this is
is consistent
consistent with
with the
the preponderance
preponderance of of patients
patients
senting
senting sign
sign ofof an
an occult
occult malignancy.
malignancy. Thus Thus metastases
metastases
having
having pulmonary
pulmonary small small cell
cell cancer.
cancer. Thirkill
Thirkill and
and col-
col­
must
must be be considered,
considered, especially
especially inin the
the older
older patient
patient pre-
pre­
leagues,319
leagu es , for
for example,
319 example, in in aa series of 10
series of 10 patients,
patients, identify
identify
senting
senting with
with uveitis
uveitis refractory
refractory to to or
or recurring
recurring after
after steroid
steroid
all
all as
as heavy
heavy smokers.
smokers.
therapy.
therapy. Although
Although the the prognosis
prognosis is is poor,
poor, asas metastatic
metastatic
The
The most
most common
common malignancy
malignancy associated
associated with
with CAR
CAR isis
disease
disease isis generally
generally associated
associated with
with advanced,
advanced, pre-termi-
pre-termi­
small cell cancer
small cell cancer of
of the
the lung,
lung, seen
seen in about 60%
in about 60% of of the
the
nal primary cancers,
nal primary cancers, thethe importance
importance of of malting
making this
this diag-
diag­
cases;
cases ; however,
however, non-small
non-small cell cell pulmonary
pulmonary cancer,
cancer, endo-
endo­
nosislies in
nosis'lies in the
the fact
fact that,
that, with
with early
early recognition,
recognition, a a consid-
consid­
metrial
metrial carcinoma,
carcinoma, breast
breast adenocarcinoma,
adenocarcinoma, cervical
cervical small
small
erable
erable amount
amount can be done
can be done toto improve
improve thethe quality
quality of
of life
life
cell carcinoma,
cell carcinoma, embryonal
embryonal rhabdomyosarcoma,
rhabdomyosarcoma, and and mela-
mela­
in
in these patients.
these patients.
noma 318 have also
nomas" have also been
been reported
reported to to be
be associated
associated with
with

PARANEOPlASTIC CAR.
PARANEOPLASTIC SYNDROMES
CAR.
SYNDROMES

Definition
Definition
Clinical
C l i n ic a l Characteristics
Characteristics

In patients with
In patients with cancer,
cancer, symptom
symptom complexes
complexes that that cannot
cannot
Characteristically,
Characteristically, patients patients present
present with with fairly
fairly rapid,
rapid, unex-unex­

be readily
be readily explained,
explained, eithereither byby local
local or
or distant
distant spread
spread of of
plained
plained vision
vision loss
loss occurring
occurring over over several
severa! weeks
weeks to to months
months

the
the tumor
tumor or or byby elaboration
elaboration of of hormones
hormones indigenous
indigenous to to
and
and often
often associated
associated with with photopsias,
photopsias, night night blindness,
blindness,

the
the tissue
tissue from
from whichwhich thethe malignancy
malignancy arose,
arose, areare called
called
positive
positive transient
transient visualvisual phenomena,
phenomena, and and visual
visual field
field dis-
dis­

turbances.
turbances. The The vision
vision lossloss frequently
frequently precedesprecedes the the diagno~
paraneoplastic syndromes.
paraneoplastic syndromes. A A number
number of of different
different malig-
malig­
diagno­

nancies produce paraneoplastic

nancies produce paraneoplastic syndromes
syndromes withwith involve-
involve­
sis
sis of
of a a systemic
systemic malignancy,
malignancy, tliUS thus making
making diagnosis
diagnosis of of

ment
ment of of neuronal
neuronal tissue-the
tissue-the cerebellum,
cerebellum, the the anterior
anterior
CAR
CAR lessless apparent.
apparent. The The time time reported
reported betweenbe tw een onsetonset of of

horn
horn cells,
cells, and
and thethe sensory
sensory root
root ganglia
ganglia toto name just aa
name just
visual
visual symptoms
symptoms and and the the diagnosis
diagnosis of of cancer
cancer varies
varies from from

aa few
few weeks
weeks to to several
several months.
316
months.v", 318, 320 Gehrs
318• 320
Gehrs and and Tied.
Tied­.
few-and
few-and in in many
many of of these,
these, the
the pathogenic
pafüogenic factor
factor isis the
the

presence of man,
man, for for example,
example, report report an an interval
interval of of 181 8 months
months in
of antibodies
antibodies to to CNS
CNS antigens.
antigens. Similarly,
Similarly, para-
in
presence para­
one
one of of their
their patients.
32o
32
neoplastic
neoplastic neuronal
neuronal degeneration
degeneration of of the
the retinal
retinal photore-
photore­ patients. º

ceptor
ceptor cells
cells causing
causing bothboth rodrod and
and cone
cone dysfunction,
dysfunction, and and
Vision
Vision lossloss isis often
often asymmetric;
asymmetric; the the presenting
presenting visual visual

acuity
acuity maymay range
range fromfrom 20/2020/20 to to light
light perception.
319 Some
319

associated
associated withwith antibodies
antibodies to to certain
certain retinal
retina! elements,
elements, has has
perception. Sorne

been
been described
described as as cancer-associated
cancer-associated retinopathy
retinopathy (CAR).
( CAR ) .
people
people reportreport frank frank nyctalopia,
nyctalopia, whereas whereas others others report
report

Melanoma-associated retinopathy
Melanoma-associated retinopathy (MAR)
(MAR) syndrome
syndrome is is an-
an­
glare
glare andand photosensitivity,
photosensitivity, possibly possibly reflecting
reflecting differences
differences

other
other visual
visual paraneoplastic
paraneoplastic condition.
condition. MAR
MAR is is very
very similar
similar
in
in the
the relative
relative involvement
involvement of of rods
rods or or cones.
eo nes. Color
Co l o r vision
vision

to
to CAR,
CAR, butbut it it is
is associated
associated with
with metastases
metastases from
from cutane-
cutane­
loss may
loss may be be present
present at at the
the time
time of of presentation
presentation or or may
may

ous
ous melanomas
melanomas and and with
with certain
certain distinguishing
distinguishing clinical
clinical
develop
develop over over thethe course
course of of tlie
the disease.
disease. Transient,
Transient, painless
painless

features.
features. Bilateral
Bilateral diffuse uveal melanocytic
diffuse uveal melanocytic proliferation
proliferation
visual obscurations,
visual obscurations, includingincluding dimming dimming of of central
central vision
vision

is
is a
a recently
recently described
described paraneoplastic
paraneoplastic entity
entity characterized
characterized
and
and loss
loss of of peripheral
peripheral vision, vision, may may last last from
from seconds
seconds to to

by aa bilateral,
by bilateral, diffuse
diffuse proliferation
proliferation ofof melanocytic
melanocytic cells cells
minutes.
minutes. Bizarre
Bizarre visual
visual phenomena,
phenomena, such such asas halos,
halos, "float-
"fl oat ­

throughout
throughout the the uvea
uvea inin association
association with
with aa systemic
systemic malig-
malig­
ing
ing tissue
tissue paper"314
paper "
314
in
in the
the eye,
eye, "swarms
"swarms of of bees"
bees " over
over the the

nant
nant neoplasm.
neoplasm.
central
central vision,314
vision.t'" and and "shimmering
"shimmering curtains" curtains" havehave been b een

reported.
repo rt ed.

History
History Visual
V isual field
fi eld changes
c h a n g e s characteristically
characteristica ll y show show initial
ini tia l

CAR
CAR was was first
first described
d e s c r i b e d by
by Sawyer
Sawyer and and associates
a s s o c i a t e s in
in midperipheral
midperipheral scotomas scotomas that that eventually
eventually lead lead to to classic
classic

1976
1976
314 in
3 14
in a a case
case series
series of of three
three patients
patients with
with small
small cell cell ring
ring scotomas
scotomas
321 with
321
with central
central sparing,319
sparing,
319
although
although there there

carcinoma
carcinoma of of tlie
the lung.
lung. TheseThese three
three older
older patients
patients had had are
are many
many variations
variations on on this
this pattern,
pattern, and and central
central defects
defects

vision
vision loss
loss with
with symptoms
symptoms before before thethe diagnosis
diagnosis of of cancer,
cancer, may
may also
also occur.
occur. Arcuate
Arcuate defects,
defects, because
because they they result
result from from

early
early visual
visual field defects of
field defects of ringlike
ringlike scotomas,
scotomas, and and retinal
retinal damage
damage to to the
the outer
outer retina,
retina, do do notnot respect
respect the the horizontal
horizontal

arteriolar
arteriolar narrowing.
narrowing. Histopathologic
Histopathologic examination
examination in in meridian.
meridian.
318 These
318
These changes
changes may may be be asymmetrical
asymmetrical between be tw een

these
these cases
cases revealed
revealed widespread,
widespread, severe severe degeneration
degeneration of of the
the two
two eyes,319
eyes,
319
and
and diagnosis
diagnosis of of the
the condition
condition can can easily
easily

the
the outer
outer retinal
retinal layers
layers and and mild
mild melanophagic
melanophagic activity. activity. be
be missed
missed if if visual-field
visual-field testing
testing is is not
not done.
done.

In 1982,
In 1 9 8 2 , Kornguth
Kornguth and and associates
associat e s
315 published
published the
315
the firstfirst The
The slit-lamp
slit-lamp examination
examination is is usually
usually norma1.3
norma l.
32121 How-
How­

report
report demonstrating
demonstrating antiretinal
antiretinal ganglion
ganglion cellcell antibodies
antibodies ever, there
ever, there are are several
several reports
reports of of patients
patients having
having vitritis
vitritis inin

in
in patients
patients withwith small
small cell ce ll carcinoma
carcinoma of of the
the lung.
lung. In In 1987,
1987, association
association with with this
this condition.
condition. ThirkillThirkill and and associates,
associate s , for for

Thirkill
Thirkill andand associates
associates
316 reported
316
reported the the isolation
isolation of of thethe 23- 23- example,
example, reportreport vitreous
vitreous cellscells in in seven
seven of of aa series
series of of eight
eight

kD
k.D CAR
CAR retinal
retinal antigen,
antigen, and and inin 1992
19 92 they
they identified
identified it ita ass patients.
patients.
319 Although
319
Although the the vitreous
vitreous reaction
reaction is is very
very often often

the
the photoreceptor
photoreceptor componentrecoverin.
component reco v erin.
317 Since
Since then,
317
then, it it mild,
mild, this
this case
case series
series included
included patientspatients with with heavy
heavy debris,
deb ris,

has
has been
been recognized
recognized that that malignancies
malignancies other other than
than pulmo-
pulmo­ 2 +
2 + cells,
cells, and
and peripheral
peripheral vitreousvi tr eous clumps
clumps of of cells.
ce ll s. Ohkawa
Ohkawa

nary
nary small
small cell
cell carcinoma,
carcinoma, and and retinal
retinal proteins
proteins otherother than than and
and associates
associates
322 report
322
re p ort a a case
case with
with mildmild bilateral
bilateral iridocy-
iridocy­

recoverin
recoverin can can bebe associated
associated with with the
the CAR
CAR syndrome.
syndrome. clitis
clitis and
and vitritis
vitritis with
with retinopatliy
retinopathy characterized
characterized by by a a mot-
mot-

s
 CHAPTER
C H A P T E R 48:
4 8 : MASQUERADE
M A S Q U E R A D E SYNDROMES:
S Y N D R O M E S : MALIGNANCIES
MAUGNANCIES

tled
tled RPE
RPE pattern,
pattern, narrowed
narrowed arterioles,
arterioles, and
and several
severa! spots
spots an
an abnormal
abnormal scotopicscotopic ERG, ERG, whereas
whereas those those with with clinical
clinical

of
of hyperpigmentation.
hyperpigmentation. features
features suggestive
suggestive of of cone
cone dysfunction
dysfunction (e.g., ( e . g . , glare
glare and
and

In
In the
the CAR
CAR syndrome,
syndrome, the
the fundus
fundus cancan appear
appear remark-
remark­ photosensitivity,
photosensitivity, decreaseddecreased acuity,
acuity, andand dyschromatopsia)
dyschromatopsia)

ably
ably normal
normal in in the
the early
early stages
stages of
of the
the disease,
disease, although
although show
show a a typically
typically abnormal
abnormal cone cone ERG.319
ERG.
319

subtle
subtle arteriolar
arteriolar narrowing
narrowing is is characteristic
characteristic
321 and
and disc
disc
321
Immunohistochemical
Immunohistochemical testing testing is is also
also required
required in in these
these

pallor
pallor mayor
may or maymay not
not be
be present.
present.
321 Although
Although mottling
321
mottling patients,
patients, to to identify
identify the the presence
presence of of the
the antiretinal
antiretinal anti- anti­

of
of the
the RPE
RPE has
has been
been described,
described, the
the appearance
appearance ofof the
the bodies.
bodies. In In anyany patients
patients suspected
suspected of of having
having CAR, CAR, and and

fundus
fundus maymay be
be completely
completely normal,319
normal, thus
thus making
making diagno-
319
diagno­ with
with nono known
known malignancy,
malignancy, a a search
search for for the the systemic
systemic

sis
sis of
of the
the disease
disease even
even more
more difficult.
difficult. malignancy
malignancy must must alsoalso bebe undertaken.
undertaken. Before Before making making the the

diagnosis
diagnosis of of CAR,
CAR, metastatic
metastatic involvement
involvement of of thethe eye,
eye, optic
optic

Pathology
Pathology nerve
nerve compression,
compression, and and chemotherapy-induced
chemotherapy-induced toxicity toxicity

Histopathologic
Histopathologic study study of
of the
the eyes
eyes inin these
these casescases reveals
reveals need
need to to be
be excluded.
excluded.

widespread,
widespread, severesevere degeneration
degeneration of of the
the outer
outer retinal
retinal lay-lay­ MAR
MAR differs
differs from from CAR CAR in in that
that it it usually
usually occurs occurs in in

ers, and
ers, and mild
mild melanophagocytic
melanophagocytic activity. activity. There
There is is "severe
"severe individuals
individuals who who have have an an established
established diagnosis
diagnosis of of cutane-
cutane­

disintegration
disintegration of of the
the photoreceptors,
photoreceptors, marked marked loss loss ofof nu-
nu­ ous
ous melanoma,
melanoma, and and it it is
is usually
usually found
found to to be be associated
associated

clei
clei from
from the the outer
outer nuclear
nuclear layer,
layer, and
and macrophages
macrophages con- con­ with
with metastases.
metastases. AlthoughAlthough cases cases havehave beenbeen reported
reported in in

taining phagocytosed granules

taining phagocytosed granules from from the the RPE,"RP E , " with
with al- al­ which
which MAR MAR occurred
occurred in in the
the absence
absence of of any
any obvious
obvious me- me­

most
most complete
complete preservation
preservation of of the
the other
other layers layers of of thethe tastasis
tastasis after
after extensive
extensive evaluation,325
evaluation,
325
caution
caution is is advised
advised in in

retina.
retina.
314 There
314
There may may bebe variation
variation on on this
this basic
basic pattern,
pattern, declaring
declaring such such patients
patients metastases
metastases free, free, since
since an an occult
occult

with
with sparing
sparing of of cones
eones being
being reported
reported on on the the histopatho-
histopatho­ metastasis
metastasis may may wellwell become
become apparent
apparent later.later.

logic
logic examination
examination of of the
the eyes
eyes ofof patients
patients with with primarily
primarily MAR patients
MAR patients are are typically
typically men,men, presenting
presenting with with shim-
shim­

rod
rod dysfunction
dysfunction clinically
clinically andand on on electroretinography
e l e c t ro r e ti n o g r a p h y mering,
mering, flickering,
flickering, or or pulsating
pulsating photopsias,
photopsias, with with progres-
progres­

(ERG).
( E R G ) . Clearly,
Clearly, then,
then, it
it seems
seems thatthat specific
specific cells cells in in the
the sive
sive visual
visual lossloss overover months.
months. Progression
Progression of of symptoms,
symptoms,

retina
retina areare being
being targeted
targeted in in this
this condition.
condition. although
although reported,
reported, appearsappears to to bebe uncommon.
uncommon. The The pri-
pri­

The
The most
most well-accepted
well-accepted mechanism
mechanism for for thethe pathogene-
pathogene­ mary
mary manifestation
manifestation in in MAR
MAR is is aa central
central visual
visual fieldfield defect,
defect,

sis
sis of
of the
the CAR
CAR syndrome
syndrome involves
involves autoimmunity
autoimmunity to to com-
com­ with
with relative
relative sparing
sparing of of the
the peripheral
peripheral visualvisual fields,
fields, and
and

ponents of
ponents of the
the retinal
retinal photoreceptors.
photoreceptors. The The most most well-well­ ERGs
ERGs showshow a a characteristic
characteristic patternpattern (similar
( similar to to congenital
congenital

recognized
recognized antigen
antigen to to which
which an an autoimmune
autoimmune reaction reaction is is stationary
stationary night night blindness)
blindness) with with a a markedly
markedly reduced reduced b- b­

produced in
produced in CAR,
CAR, especially
especially in in association
association with with small
small cell
cell wave in
wave in the
the presence
presence of of a a normal
normal dark-adapted
dark-adapted a-wave. a-wave.
326
326

carcinoma
carcinoma of of the
the lung,
lung, isis the
the 234.D
234.D antigen
antigen recoverin,
recoverin, Such
Such a a pattern
pattern localizes
localizes the the pathology
pathology to to the
the inner
inner retinal
retinal

which
which is is a
a component
component of of the
the photoreceptor
photoreceptor cells. cells. Experi-
Experi­ plexes
plexes rather
rather than than the the photoreceptors.
photoreceptors. Indeed, Indeed, MAR MAR is is

mental
mental evidence
evidence suggests
suggests that
that there
there is is aberrant
aberrant expres-
expres­ not
not associated
associated with with recoverin
recoverin hypersensitivity,
hypersensitivity, and and since
since

sion
sion of of recoverin
recoverin in in pulmonary
pulmonary small small cell cell carcinoma,
carcinoma, it
it commonly
commonly develops develops long long after
after the
the primary
primary cancer cancer is is

which
which results
results inin sensitization
sensitization to to this
this photoreceptor
photoreceptor com- com­ discovered,
discovered, it it is
is thought
thought to to involve
involve a a different
different mechanism.
mechanism.

ponent. 323 Retinal

ponent. 323 Retinal proteins
proteins other
other thanthan the the 23-kD
23-kD antigen
antigen Studies
Studies havehave shownshown the the presence
presence of of immunoglobulins
immunoglobulins

have
have also
also been
been implicated
implicated in in CAR,
CAR, including
including 40-kD, 40-kD, 45- 45- that
that react
react selectively
selectively with with thethe bipolar
bipolar ,cells
cells of
of thethe retina.
retina.
327
327

kD, and
kD, and 60-kD
60-kD proteins,
proteins, none
none of of which
which have have beenbeen cloned
cloned Identification
Identification of of MAR
MAR is is important,
important, asas it
it could
could be be the
the first
first

to
to provide
provide the the exact
exact protein
protein sequence
sequence of of the
the retinal
retinal anti-
anti­ sign of
sign of metastases
metastases in in aa patient
patient with
with aa seemingly
seemingly stable stable or
or

gen
gen involved.
involved.
324
324
cured
cured condition.
condition.

Bilateral
Bilateral diffuse
diffuse uveal
uveal melanocytic
melanocytic proliferation
proliferation is is an-
an­

Diagnosis
Diagnosis other
other condition
condition that
that frequently
frequently presents
presents with
with visual
visual symp-
symp­

The
The diagnosis
diagnosis cancan be
be difficult,
difficult, especially
especially when when the
the ocular
ocular toms
toms prior
prior toto the
the diagnosis
diagnosis of of the,
the systemic
systemic malignancy.
malignancy.

presentation occurs
presentation occurs before
before the the systemic
systemic neoplastic
neoplastic proc-
proc­ Dilated
Dilated episcleral
episcleral vessels,
vessels, early
early maturation
maturation of of cataracts,
cataracts,

ess
ess has
has been
been discovered.
discovered. Jacobson
Jacobson and and associates
associates
321 have
321
have and
and moderate
moderate vitritis
vitritis have
have been
been described
described as as typical
typical ocu-
ocu­

described
described a a characteristic
characteristic triadtriad of of photosensitivity,
photosensitivity, ringring lar
lar features,
features, with
with proliferation
proliferation of of choroidal
choroidal nevus-like
nevus-like

scotomas,
scotomas, and and attenuation
attenuation of of retinal
retinal arteriolar
arteriolar caliber.
caliber. lesions, and
lesions, and the
the presence
presence of of round,
round, yellow-orange
yellow-orange lesionslesions

These,
These, together
together with
with the
the other
other features
features described,
described, espe-
espe­ at
at the
the level
level of
of the
the RPE,
RPE, associated
associated with
with serous
serous macular
macular

cially when
cially when they
they occur
occur in in the
the older
older patient
patient and
and when
when detachment.
detachment. Fluorescein
Fluorescein angiography
angiography showsshows numerous
numerous

abnormalities
abnormalities on on the
the examination
examination of of the
the eye
eye are
are inconsis-
inconsis­ window
window defects
defects ofof the
the RPE
RPE atat the
the posterior
posterior pole.
pole. Histo-
Histo­

tent
tent with
with the
the degree
degree of of symptomatic
symptomatic disability disability ofof the
the pathologic
pathologic examination
examination shows shows choroidal
choroidal thickening
thickening with with

patient, should
patient, should raise
raise the
the suspicion
suspicion of of CAR.
CAR. proliferation
proliferation of of benign-looking,
benign-looking, spindle-shaped
spindle-shaped melano- melano­

The
The ERG pattern can
ERG pattern can bebe extremely
extremely sensitive
sensitive in
in making
making cytes.
cytes. This
This condition
condition should
should be be suspected
suspected 'in 'in patients
patients

the
the diagnosis
diagnosis of of CAR,
CAR, showing
showing reduced reduced amplitudes
amplitudes or or with
with multiple,
multiple, bilateral
bilateral uveal
uveal nevi,
nevi, with
with serous
serous retinal
retinal

being totally
being totally flat
flat in
in these
these patients;
patients; progression
progression of of the
the detachment,
detachment, vitritis,
vitritis, and
and cataracts.
cataracts. Diagnosis
Diagnosis is is important
important

disease
disease may
may bebe associated
associated withwith progressive
progressive reductions
reductions inin as
as it
it could
could lead
lead to to the
the early
early detection
detection and and therefore
therefore

ERG
ERG amplitudes.
amplitudes.
319 On
On the
319
the other
other hand, hand, visual
visual acuity
acuity may
may improved
improved prognosis
prognosis of of aa malignancy.
malignancy.

be normal
be normal in in the
the presence
presence of of aa flat
flat ERG,
ERG, indicating
indicating severe
severe

retinal dysfunction
retinal dysfunction with
with relative
relative macularmacular sparing.
sparing. The
The Treatment
Treatment
relative
relative rodrod and
and cone
cone dysfunction
dysfunction in in CAR
CAR varies
varíes from
from Several
Several treatment
treatment modalities
modalities have
have been
been tried
tried with
with incon-
incon­

patient to
patient patient: Patients
to patient: Patients with
with clinical
clinical problems
problems associ-
associ­ sistent
sistent results.
results. Treatment
Treatment isis based
based on
on the
the premise
premise that
that

ated
ated with
with rod
rod dysfunction
dysfunction (e.g.,
( e . g . , nyctalopia,
nyctalopia, prolonged
prolonged CAR
CAR isis an
an autoimmune
autoimmune condition,
condition, and
and therefore
therefore immu-
immu­

dark
dark adaptation,
adaptation, andand peripheral
peripheral or or ring
ring scotomas)
scotomas) show
show nosuppressive
nosuppressive therapies
therapies are
are the
the mainstay
mainstay ofof treatment.
treatment.
1m CHAPTER
C H A P T E R 48:
48: MASQUERADE
M A S Q U E RA D E SYNDROMES:
S Y N D R O M E S : MALIGNANCIES
MAUGNANCIES

Prednisone,
Prednisone, plasmapheresis,
plasmapheresis, andand intravenous
intravenous immuno-
immuno­
19.
1 9 . Akpek
Akpek EK, EK, Ahmed
Ahmed I, I, jakobiec
Jakobiec FA, FA, et et al:
al: Intraocular-central
Intraocular-central ner- ner­

vous
vous system
system lymphoma:
lymphoma: Clinical Clinical featui-es,
features, diagnosis
diagnosis and and outcomes.
outcomes.
globulin
globulin have
have been
been used,
used, with
with thethe antiretinal
antiretinal antibody
antibody
327 It Ophthalmology
Ophthalmology 1999;106:1805-1810.
1 9 9 9 ; 10 6 : 1 8 0 5 - 18 1 0 .
titers
titers used
used to
to monitor
monitor treatment.
treatment. It has
has been
been suggested
suggested
327

20. Schanzer
20. Schanzer CM, CM, FontFont RL, RL, O'Malley
O'Malley RE:. RE: Primary
Primary ocular ocular malignant
rnalignant

that
that if
if antibody
antibody titers
titers do
do not
not fall
fall to
to baseline
baseline with
with a
a particu-
particu­ lymphoma
lymphoma associated associated with with the the acquired
acquired immune immune deficiency
deficiency syn- syn­

lar
lar immunosuppressive
immunosuppressive agent,agent, changing
changing to to other
other immu-
immu­ drome.
drome. Ophthalmology
Ophthalmology 1991;98:88-91. 1 9 9 1 ; 9 8 : 8 8 - 9 1.

nosuppressive
nosuppressive measures
measures may
may be
be necessary.
necessary.
21. johnson
21. Johnson BL: BL: Intraocular
Intraocular and and central
central nervousnervous system system lymphoma
lymphoma in in

aa cardiac
cardiac transplant
transplant recipient.
recipient. Ophthalmology
Ophthalmology 1992;99:987-992. l 992;99:987-992.
The
The treatment
treatment for
for patients
patients with
with thethe MAR
MAR syndrome
syndrome ISis
22. Appen
22. Appen RE: RE: Posterior
Posterior uveitisuveitis and and primary
primary cerebral cerebral reticulum
reticulum cell cell
similar
similar toto that
that of
of CAR.
CAR. sarcoma. Arch
sarcoma. Arch Ophthalmol
Ophthalmol 1975;93:123-124.
1975;93:123-124.

23.
23. Rockwood
Rockwood Ej, EJ, Zakov
Zakov ZN, Bay JW: Combined
ZN, Bay]W: Combined malignant malignant lymphoma lymphoma

Prognosis
Prognosis of
of thethe eyeeye and and CNS CNS (reticulum-cell
(reticulum-cell sarcoma). s a r c o m a ) . jJ Neurosurg
Neu rosurg

The
The visual
visual prognosis
prognosis of of paraneoplastic
paraneoplastic retinopathies,
retinopathies, both both
1984;61:369-374.
1984;61:369-374.

24. Henry
24. Henry jM, JM, Heffner
Heffner RR RR jr, Jr, Dillard
Dillard SH, SH, et et al:al: Primary
Primary malignantmalignant
CAR
CAR and
and MAR, MAR, is is generally
generally poor,
poor, with with different
different treatment
treatment
lymphomas
lymphomas of of the
the central
central nervous
nervous system. system. Cancer Cancer 1974;34:1293-
1974;34:1293-
modalities
m o d a l it i e s showing
showing inconsistent
i n c o n s i s t e n t results.
r e s u l t s . Patients
P a t i e n t s may
may
1302.
1302.

show
show no no response
response eveneven on on plasmapheresis,
plasmapheresis, presumably presumably 25. Murray
25. Murray K., K., Kun
Kun L, Cox JW: Primary
L, Cox]W: Primary malignant malignant lymphoma lymphoma of of the
the

because
because once once retinal
retinal structures
structures have have beenbeen irreversibly
irreversibly central
central nervous
nervous system:
system: Results
Results of of treatment
t:reatment of of 111 1 cases
cases and and review
review

damaged,
damaged, immunosuppressive
immunosuppressive therapy therapy will will not not reverse
reverse
of
of the
the literature.
literature. j J Neurosurg
Neurosurg 1986;65:600-607.
1986;65:600-607.

26. Char
26. Char Dj, DJ, Ljung
Ljung BM, BM, MillerMiller T, T, Phillips
Phillips T: T: Intraocular-CNS
Intraocular-CNS lym- lym­
the
the change.
change. However,However, there
there have have beenbeen reportsreports of of both
both
phoma
phoma (ocular ( ocular reticulum
reticulum cell cell sarcoma):
sarcoma): Diagnosis Diagnosis and and manage-manage­
CAR
CAR andand MAR MAR patients
patients who who have have improved
improved with with treat-
treat­
ment.
ment. Ophthalmology
Ophthalmology 1988;95:625-630.
1988;95:625-630 .

ment."? and
ment,327 and of of CAR
CAR patients
patients who who failed
failed a a trial
trial of
of predni-
predni­ 27. Baumann
27. Baumann MA, MA, Ritch
Ritch PS, PS, Hande
Hande KR, KR, et et al:
al: Treatment
Treatment of of intraocular
intraocular

sone
sone and
and plasmapheresis
plasmapheresis but but responded
responded dramatically
dramatically to to lymphoma
lymphoma with with high
high dose dose Ara-C.
Ara-C. Cancer Cancer 1986;57:1273-1275.
1986;57:1273-1275.

intravenous
intravenous immunoglobulin.
immunoglobulin.
328 328 28. de
28. de Smet
Smet ME, ME, Nussenblatt
Nussenblatt RE, RB, Davis
Davis jL, JL, etet al:al: Large
Large cell cell lymphoma
lymphoma

masquerading
masquerading as as aa viral
viral retinitis.
retinitis. Int Int Ophthalmol1990;14:413-417.
Ophthalmol 1 9 9 0 ; 1 4 : 4 1 3 - 4 1 7 .

29.
29. Guz.ak
Cuzak SV: SV: Lymphoma
Lymphoma as as a a cause
cause of of hyphema.
hyphema. Arch Arch Ophthalmol
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 CHAPTER 48:
CHAPTER 48: M A S Q U E RA D E S Y N D R O M E S : MAUGNANCIES

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