SURVEY OF OPHTHALMOLOGY VOLUME 27-NUMBER 4-JANUARY-FEBRUARY 1983

REVIEW

Ocular and Orbital Involvement in Leukemia

MARILYN C . KINCAID, M .D ., AND W . RICHARD GREEN, M .D .

Eye Pathology Laboratory, Wilmer Ophthalmological Institute and Department of Pathology, The Johns
Ilopkins Hospital, Baltimore, Maryland

Abstract . Leukemia may involve almost any ocular tissue, by direct infiltration, by hemorrhage,
and by ischemic changes . Both acute and chronic leukemia can cause ocular signs, either initially
or later in the disease process ; the clinical features and pathologic correlations of this involvement
are reviewed . Also, various chemotherapeutic agents used to treat leukemia may cause ocular
toxicity . Recently, bone marrow transplants have been performed more frequently in an attempt
to prolong patient survival ; if graft-versus-host disease results, one symptom is' dry eyes from
alacrima . Superimposed infection due to immunosuppression can occur from the disease itself or
from treatment . Recognition by the ophthalmologist of the various ocular signs is important in
assessing the course and prognosis of leukemia . (Surv Ophthalmol 27 :211-232, 1983)

Key words. anterior chamber • cornea • graft versus host

immunosuppression • lacrimal duct • lacrimal gland
leukemia • optic nerve • orbit • retina • uvea • vitreous

t is a truism that the eye often reflects the disease
I states of the body, and this is certainly so for the
leukemias .
Before the advent of bone marrow biopsy, oph-
thalmologists were routinely consulted to assist in
the diagnosis of leukemia ." They looked for leuke-
mic retinopathy, which was often present, although
frequently asymptomatic . The bone marrow biopsy
has tended to replace the ophthalmologist in con-
firming the diagnosis, but he or she is still likely to
encounter patients with leukemia at all stages of the
disease . Indeed, eye symptoms may be the initial
presentation of leukemia .
Therefore, a review of ocular involvement in leu-
kemia is appropriate, especially as survival time for
patients with acute leukemia has increased dramati-
cally with chemotherapy and bone marrow trans-
plantation . Current estimates of leukemic involve-
ment of the eye at some point in the course of the
disease range as high as 90% of cases ."
211
I. Systemic Leukemia and Classification
The leukemias may be divided into acute and
chronic types, based on differences in presentation
and clinical course . The acute leukemias present
with the signs and symptoms of anemia, hemor-
rhage, and infection, and also with infiltration of the
lymph nodes, spleen, and liver . If acute leukemia is
untreated, death ensues usually a few months after
diagnosis . Chemotherapy, however, has allowed
prolonged remission, especially in acute lymphocyt-
ic leukemia which has a 50% core rate in childhood .
The leukemias are also classified by cell type .
Acute lymphocytic leukemia (ALL) probably arises
from lymphoid tissue, although its first clinical
manifestations occur after abnormal population of
the bone marrow . Acute myelocytic leukemia
(AML) arises from the marrow hematopoietic stem
cell, or from one of the more differentiated marrow
cells, and it is named for that cell . Thus, one can


212 Surv Ophthalmol 27 (4) January-February 1983 KINCAID, GREEN

designate various cell types of leukemia ; acute mye- TABLE I

loblastic, acute monocytic, etc ."," With chemo- Number (Percent) of Involved Eyes in Leukemia
therapy, a 15 to 20% cure rate has been achieved, Wilmer Institute, /92 1980
and this rate may improve with further use of bone All Acute Chronic
marrow transplants (Dr . Rein Saral, personal com- Interval Leukemias Leukemia Leukemia
munication, April I, 1982) . 1923-1947 38/41 (93%) 17/19 (89%) 19/20 (95%)
The chronic leukemias have a far more indolent 1948-1960 57/72 (79%) 40/46 (87%) 17/24 ((71%)
course, and the presenting symptoms are more 1961-1970 31/38 (82%) 25/31 (81%) 6/7 (86%)
1971-1975 71/96 (74%) 49/67 (73%) 17/23 (74%)
vague . Indeed, the diagnosis may be made inciden- 1976-1980 87/110 (79%) 59/70 (84%) 14/23 (61%)
tally when a blood smear is obtained for other pur-
poses . The chronic leukemias are generally diseases Totals 284/357 (80%) 190/233 (82%) 73/97 (75%)
of older persons and are rare in those less than 20
years old . Chemotherapy does not appear to pro-
long survival, although it may improve the quality
of life . pairs of eyes were from patients with acute leuke-
Chronic myelocytic leukemia (CML) presents mia, and 190 (82%) showed ocular involvement . Of
with symptoms of fatigue and weight loss . Survival 97 patients with chronic leukemia, 73 (75%) had
time ranges from I to 10 years, with a median of 2'/2 some kind of leukemic eye involvement . The re-
to 3 years, and the disease can be easily managed maining patients included 27 who had had bone
until a "blast crisis" occurs . About 60 to 80% of marrow transplants and 27 others who had leuke-
patients develop blast crisis, in which the disease mia that was not classified as acute or chronic . By
suddenly behaves like AML and is unresponsive to contrast, in another recent autopsy series of 101
chemotherapy . patients who died of leukemia, only 28% had ocular
Chronic lymphocytic leukemia (CLL) presents involvement (Nelson CC, Spector B, Klintworth
with infection in about 65% of patients, because the GK, Lab Invest 46: 61A, 1982) .
leukemic cells do not form antibodies adequately in Despite the fact that our series spans more than
response to antigen stimulus . Both chemotherapy fifty years and that therapy for the leukemias has
and radiation therapy have been used with some changed drastically, there was relatively little
success, especially if begun early in the course of the change in the frequency of ocular involvement in
disease .", as general (see Table 1) or in the frequency of specific
The cells ofCLL are predominantly small B-lym- ocular tissue involvement . A clinical series assessing
phocytes which usually do not secrete immunoglob- ocular involvement in leukemia might better reflect
ulin . Most patients with CLL have decreased levels continuing advances in treatment and prolongation
of immunoglobulin, as noted above, but a small of survival ; however, we know of no such recent
fraction have a type of Waldenstrom's macroglobu- series .
linemia, with monoclonal IgM secretion ." Survival Leukemic involvement in the various ocular tis-
time is related to the extent of disease, with those at sues is described below .
Stage 0 (lymphocytosis only) having a median sur-
vival of 10 years, and those at Stage IV (hepato-
splenomegaly, anemia, and thrombocytopenia) sur-
viving a median of I to 3 years ."

II . Ocular Involvement : Methods,

Results and Review
The eye is involved, directly or indirectly, far
more often in the acute leukemias than in chronic
cases . In Allen and Straatsma's'series, 80% of eyes
involved with the leukemia process were from pa-
tients with acute leukemia, although these authors
indicated that chronic leukemia can involve the eye
during the disease course, with later resolution .
We reviewed all postmortem eyes obtained at the
Wilmer Institute from 1923 through 1980 (Table 1) .
In all, there were 18,389 pairs of eyes . Of those, 384 Fig . 1 . Hemorrhages with white centers (arrows) in retina
(2%) were from leukemia patients . Of these, 233 of a 19-year-old man with acute myelogenous leukemia .
OCULAR AND ORBITAL INVOLVEMENT IN LEUKEMIA
Fig . 2. E .P . 31209 . This patient was a 39-year-old white
woman with CML diagnosed two years before death .
Top : Gross ocular specimen showing diflitse hemorrhages
(arrows) and leukemic infiltrates (arrowheads) through-
out the retina . Bottom : Sub-internal limiting membrane
hemorrhage containing leukemic cells (hematox)lin and
eosin, x 60) .
A . RETINA
The retina clinically shows leukemic involvement
in some form more often than any other ocular tis-
sue . Duke-Elder" estimated that up to 90% of all
persons with leukemia will show fundus changes at
some point in the disease course . In chronic leuke-
mia, the changes can resolve .'
One of the first changes is that the veins become
more dilated and tortuous .' Both arteries and veins
become more yellowish, reflecting the decreased red
cell count and increased white cell count' Hemor-
rhages may occur at all levels of the retina, usually
in the posterior pole, and may extend into the vitre-
ous . They may be round or flame-shaped, and often
have a white component (Fig . 1) . The white area
consists of leukemic cells and debris, platelet-fibrin
aggregates, or septic emboli . 27
213
Fig . 3 . E .P . 20144 . A 45-year-old white woman had acute
blastic leukemia . The brain was normal by postmortem
examination, and she had had no clinical evidence of
CNS leukemia . Grossly and microscopically, she had
areas of inner retinal infarction with axonal swelling . The
nerve fiber layer of the retina is markedly thickened (be-
tween arrowheads) and contains numerous cytoid bodies
(arrows) . Hemorrhage (asterisk) is present (hematoxylin
and eosin, x 245) .
Histopathologic examination discloses discrete
and diffuse hemorrhage and leukemic infiltrations .'
The hemorrhages and infiltrates are both found at
all levels of the retina, but especially in the inner
layers, with local tissue destruction . The infiltrates
are aggregates of leukemic cells that are usually, but
not always, seen with surrounding hemorrhage ."
The smaller infiltrates tend to be perivascular .
In our series, 106 pairs of eyes (30%) showed
some type of retinal involvement . Of those, 86 pairs
(81 %) had hemorrhages, with or without white cells
in the hemorrhage (Fig . 2) .
Cotton-wool spots are often present with leuke-
mia and are probably due to ischemia from anemia,
hyperviscosity, or leukemic infiltration . Nine pa-
tients in our series had cytoid bodies histopathologi-
cally, and all but one of these had had acute leuke-
mia (Fig . 3) . Gray-white streaks alongside retinal
vessels are also common,' and may represent peri-
vascular infiltration of leukemic cells (Fig . 4) .
Massive leukemic infiltrates, often with accompa-
nying hemorrhage, may destroy the retinal architec-
ture partially or completely (Figs . 5 and 6) . In our
series, such tumors were seen in earlier cases prior
to the development of modern chemotherapy .
Less common manifestations include microan-
eurysms, which tend to be peripheral, in the chronic
leukemias of both the lymphocytic and monocytic
types . The presence of microaneurysms does not
correlate with the hemoglobin level or platelet


214 Sure Ophthalmol 27 (4) January-February 1983 KINCAID, GREEN

count, but may be related to increased viscosity

from the elevated white cell count . Some authors
speculate that continued elevated WBC may lead to
ischemia and neovascularization . 53
Only one patient in our series had retinal capil-
lary microaneurysms ; these were demonstrated by
trypsin digestion from a woman who had CML
(Fig . 7) . Interestingly, this was also the only patient
with a chronic leukemia who had cotton-wool
patches, supporting the theory ofischemia as patho-
genesis . The apparently low number of patients
with microaneurysms is due in part to the fact that
only a few eyes in our series were subjected to tryp-
sin digestion .
In a separate series" of 40 patients with leukemia
whose eyes were studied by trypsin digestion in this
laboratory, none of the 21 patients with acute leuke-
mia had microaneurysms . Three of 10 with CLL
had microaneurysms, and 7 of 9 with CML had Fig . 4 . E .P . 375 . A 30-month-old white boy died (two
months after hospital admission) of acute lymphoblastic
microaneurysms . 2"
leukemia in 1924 . The lymph nodes, bone marrow, and
Three patients, all with chronic myelogenous leu- lacrimal gland were diffusely involved, but the brain was
kemia, have been reported to have peripheral ret- normal . There was no record of an eye examination . The
inal neovascularization similar to that seen in sickle retina shows a diffuse perivascular infiltrate of blast cells
cell anemia ." ' 1 .72 In each case, the white cell count (arrows) (hematoxylin and eosin, x 140) .
was greater than 250,000/cu turn . One patient had
microaneurysms in both eyes, with vitreous hemor-
rhage in one eye ; the other eye had received laser patient with chronic myelocytic leukemia but with a
photocoagulation therapy . No hemorrhage oc- much lower white count (33,700/cu mm) and pe-
curred in that eye, although some of the neovascular ripheral neovascularization . This woman's platelet
tufts persisted ." Little's 62 patient had massive vitre- count was elevated to 988,000, and those authors
ous hemorrhage in one eye . Morse and Mc- believed this was a factor in the development of
Cready's 72 patient had bilateral sea-fan-like neovas- neovascularization . However, since the patient also
cularization also, but no vitreous hemorrhage, and had had diabetes for I l years, and since diabetes
did not receive laser treatment . may lead to peripheral neovascularization without
More recently, Leveille and Morse" reported a neovascularization at the posterior pole,s' the diabe-

Fig . 5 . E .P . 31209 (same patient

shown in Fig . 2 .) There has beenn
destruction of inner retina by a mas-
sive infiltrate of leukemic cells, with
hemorrhage . Outer retinal elements
(between arrows) are somewhat
better preserved . In this area, the
retina is detached by another large
infiltrate . The choroid contains a
few leukemic cells within vessels
(hematoxylin and eosin, x 130) .
OCULAR AND ORBITAL INVOLVEMENT IN LEUKEMIA 215

tes may have played a role in the development of
peripheral new vessels .
None of the postmortem eyes in our series had
neovascularization . Now that better control of the
white count can be achieved with leukemia therapy,
blood viscosity and resultant ischemia can be better
controlled, and neovascularization would therefore
seem to be less likely than in earlier years .
The more common manifestations of leukemic
retinopathy, such as venous dilatation, hemor-
rhages, and cotton-wool spots, are not unique to
leukemia ; similar findings are seen in severe ane-

Fig. 6. E .P . 30259 . This 33-year-old white woman died after a 7-month history of acute myelogenous leukemia with an
intracranial hemorrhage . Leukemic infiltration of the dura was found at autopsy . Left : There is elevation and disruption
of overlying retina by a massive infiltrate ofleukemic cells . Right : A large infiltrate ofleukemic cells, and hemorrhage, has
detached and partly destroyed overlying retina . Some areas of necrosis (asterisk) are present (hematoxylin and eosin ; A,
x 130 : B, x 30) .

Fig . 7. E .P. 43347 . A 43-year-old white woman was diagnosed as having chronic myelogenous leukemia by ,bone-marrow
aspiration . I8 months later, she developed a blast crisis unresponsive to therapy and died less than a month later . The
brain was normal by postmortem examination, but both eyes were found to have capillary mic oaneurysnis throughout
the retina . Left : Low-power view of a trypsin-digestion preparation of retinal vessels, showing saccular (arrowhead) and
fusiform (arrow) microaneurysms . Some of the capillaries arc acellular (asterisks) (periodic acid-Schiff, x 75) . Right :
High-power view of a fusiform aneurysm (asterisk) . There is a decreased number of endothelial cells (arrows) and a lesser
decrease of pericytes (arrowheads) (periodic acid-Schlff; A, x 75 : B, x 320) .

216 Surv Ophthalmol 27 (4) January-February 1983
mia, and are thought to be due to vascular stasis and
hypoxia . 38 .47 However, three studies have reported
no close correlation between retinal involvement
and the RBC, WBC, and platelet levels . 21,64,86
Culler" showed that extreme leukemic anemia
was often associated with a low platelet count, and
that the combination made hemorrhage more likely,
but hardly inevitable . He theorized that the abnor-
mal leukocytes invaded the choroid and retina from
the bloodstream, causing local venous sludging and
obstruction, and proliferated in situ .
The study by Robb et a1 86 showed no correlation
between retinal hemorrhage and the blood profile in
acute leukemia, but it was found that an increased
white cell level predisposed to leukemic retinal infil-
tration . There were eight patients with leukemic
infiltrates who had a mean white cell count of
288,000/cu mm, and 52 patients without infiltrates
who had a mean white cell count of 21,500/cu mm .
However, in a study of chronic myelogenous leu-
kemia, Mahneke and Videboek64 found no relation
between any aspect of retinal involvement and the
blood picture . Those authors also studied 24 pa-
tients who each had a combination of hemoglobin
level of 8 or less and platelet level of 50,000 or less ;
they found retinal hemorrhage in 15 patients, but no
hemorrhage in the other 9 . Certainly, the retinal
appearance is that of stasis and hypoxia, but the
concurrent blood count may not be consistent . It
may be that the blood profile varies during the
course, and the emergence of the fundus findings
may be delayed, correlating better with the blood
cell counts of a month or more previously .
Generally, the internal limiting membrane acts as
an effective barrier to leukemic cell infiltration ."
However, on occasion leukemic cells do invade the
vitreous, possibly emerging from the optic nerve
head . Reese and GuyMi first mentioned leukemic
cells in the vitreous in the absence of hemorrhage .
Swartz and Schumann 95 reported such a case, in
which the patient, in clinical remission from acute
lymphoblastic leukemia, had lymphoblasts in the
vitreous diagnosed by examination of a specimen
obtained by pars plana vitrectomy . Newman et a176
also demonstrated leukemic cells in the vitreous in
an eye that had been enucleated immediately after
vitreous aspiration .
Three cases from our series had vitreous involve-
ment without massive retinal hemorrhage ; all had
diffuse retinal infiltration which had broken
through into the vitreous .
Recently, a vitreous aspirate from a 3-year-old
boy with ALL was studied in our laboratory, 24,35
This patient had developed retinal and vitreous
hemorrhages, neovascularization of the disc of the
right eye, and vitreous infiltration (Fig . 8) . This
KINCAID, GREEN
i
Fig . 8. E .P. 51001 . A 3-year-old boy with known ALL
presented with decreased vision and hazy ocular media .
Since ocular involvement by leukemia could not be ruled
out, a vitreous aspiration was performed . Hyperchroma-
tic cells with nuclear-cytoplasmic disproportion and mild
nuclear membrane indentation (membrane filter, modi-
fied Papanicolaou ; all three, x 2000) . [Published with
permission from Retina 1 :121-149, 1981 ; and 2 :61-64,
1982 . Copyright by J .B . Lippincott Co .]
patient is unusual because the disease was an acute
leukemia, the neovascularization was at the disc,
and neither cell count nor platelet count was
elevated .24
B . CHOROID
Although the retina may be the ocular tissue most
often involved clinically, on histopathologic exami-
nation the choroid shows leukemic infiltration most
consistently . 9 Some degree of choroidal involvement
was seen in 85% of eyes with any ocular manifesta-
tions of leukemia .' It is almost never clinically ap-
parent, however.
A total of 65% of leukemic patients in our series,
(232 out of 357 pairs of eyes) showed some degree of
choroidal infiltration . This figure was remarkably
independent of the type of leukemia, varying from a
low of 59% (32/54 cases) in CML to a high of 68%
(52/76 cases) in ALL . Over the years, the total
number of eyes with choroidal involvement has de-
clined from 80% to 55%, and the decline is similar
for the different types of leukemia .
On histopathologic examination, the choroid
may be thickened to many times normal at the pos-
terior pole (Fig . 9) . The infiltration by leukemic
cells tends to be perivascular, but may be patchy or
diffuse . 3 " ° '5 The overlying RPE may show secon-
dary alterations, including atrophy, hypertrophy,
and hyperplasia, with migration into the retina
OCULAR AND ORBITAL INVOLVEMENT IN LEUKEMIA 217

Fig. 9. E .P . 41973 . A 10-year-old

white girl was diagnosed as having
AML . Two years later, she devel-
oped headaches and vomiting, with
left-sided seizures, but the optic
discs were normal . She later devel-
oped a marrow relapse, and she died
two months after developing the
CNS symptoms . Examination of the
brain showed a large subdural he-
matoma and leukemic infiltration of
the meninges . Top : There is a dif-
fuse leukemic infiltration of the
choroid posteriorly (asterisk), with
secondary changes in the RPE
(arrowhead) . A mild episcleral infil-
trate is present (arrow) . Bottom :
Higher magnification of the leuke-
mic choroidal infiltrate, showing the
malignant cells with variable-sized
nuclei and scanty cytoplasm (hema-
toxvlin and eosin : A . x 55 ; B, x
330) .

ally, these defects progress to a fine or coarse clump-

ing of the RPE ."
Diagnosis may be difficult when there is diffuse
choroidal thickening without nodularity . This is
similar to the problem of diagnosing a flat melano-
ma 10 or diffuse intraocular pseudotumor .""

C . IRIS AND ANTERIOR SEGMENT

(Fig . 10) . There may be secondary photoreceptor
cell loss, drusen formation, serous detachment (Fig .
Iris infiltration by leukemic cells is not always
clinically evident . It occurs along with involvement
of the choroid and ciliary body .' Clinical disease is
characterized by change in iris color ., 7" a pseudohy-
popyon which is gray-yellow,"and anterior seg-
ment involvement with elevated intraocular pres-
sure ."" The first presenting sign may he a change
in iris color 2 5 Usually, clinically apparent involve-
ment occurs with ALL,'' -'- ' fl- 10 but it may

11), and cystoid retinal edema (Fig . 12) .
When choroidal involvement is evident clinically,
it usually presents as a serous retinal detachment,
generally shallow and at the posterior pole . These
detachments have been reported in CLL, 75
ALL, 12 .102 CML, 4' and AML . 39 They are sometimes
the first observed manifestation of the leukemic
process ."' 7 Fluorescein angiography of the exuda-
tive detachments demonstrates myriad diffuse leak-
age points at the level of the RPE 57 (Fig . 13) . This
fluorescein pattern, with leakage from pinpoint
RPE defects, also can be seen in ocular malignant
melanoma, Vogt-Koyanagi-Harada syndrome,
metastatic tumor, and posterior scleritis 5 7 Eventu-
also occur with CLIP 7 or leukemia of myeloid ori-
gin ." Leukemia can also be a cause of spontaneous
hyphema in children . 44 .79,10f,
Increased intraocular pressure may be present,
and can be high enough to cause the signs and
symptoms of acute glaucoma, but with an anterior
chamber of normal depth .", Increased intraocular
pressure is sometimes the presenting symptom of
leukemia, even without overt iris changes or other
ocular manifestations ."
Ridgway et al" reported nine patients with
anterior segment involvement ; all had or developed
evidence ofCNS leukemia . Ocular signs and symp-
toms included change in iris color, secondary glau-


218 Surv Ophthalmol 27 (4) January-February 1983 KINCAID, GREEN

coma, photophobia, and decreased visual acuity .

With proper technique, the presence of malignant
cells can be verified by aspiration of the anterior
chamber pseudohypopyon . 35,68,77,%j m We have been
able to demonstrate leukemic cells by anterior
chamber tap in a patient with a history of previous
CNS relapses who presented with a small pseudohy-
popyon (Fig. 14) ."
On histopathologic examination, the iris may
show diffuse involvement, but especially at the root
and sphincter .' ,'"` The cells apparently proceed
from the ciliary body . The trabecular meshwork
may also show infiltration, which is presumably the
cause for the elevated intraocular pressure ."
In our series of 384 postmortem cases, only six
showed iris infiltration, and this was very mild . One
patient in our series showed an infiltrate in the an-
terior chamber angle and around Schlemm's canal,
as in Rowan and Sloan'ses case ; however, there was
no record of an intraocular pressure measurement Fig . 10 . E .P . 44108 . This 77-year-old woman had a white
(Fig . 15) . count of over 400,000/cu mm and a diagnosis of "aggres-
sive" CLI . was made . Examination of the spinal fluid was
negative for cells . On postmortem examination the brain
D. OPTIC NERVE AND CENTRAL NERVOUS
was unremarkable . The choroid shows moderate infiltra-
SYSTEM tion by malignant cells (arrows), and there are leukemic
Prior to the development of chemotherapy for cells within blood vessels . The overlying RPE shows areas
acute leukemia, death usually came swiftly . As a ofhypopigmentation (asterisk) and cystic change (arrow-
head) (hematoxylin and eosin, X 215) .
result of increased survival times, however, involve-
ment of the central nervous system became more
frequent . Shaw and coworkers 91 described the clini- acute leukemia, they advocated prophylactic ther-
cal entity of CNS leukemia, which may appear even apy to the CNS and posterior pole of the eye .
when the bone marrow is in remission . The diagnosis is made by finding leukemic cells in
Ridgway and coworkers 85 observed that the cen- the spinal fluid, since they infiltrate the arachnoid .
tral nervous system is a pharmacologic "sanctuary" Usually CNS leukemia occurs in children, and usu-
that is less accessible to systemic chemotherapy . For ally in cases of acute lymphoblastic leukemia, but

Fig . 11 . E .P. 43271 . A 71-year-old

white woman presented with bi-
lateral serous retinal detachments
and mental changes. No diagnosis
was obtained until after death, when
extensive infiltration by leukemic
cells was found . The choroid was
diffusely infiltrated posteriorly, with
tumor cells also in the choriocapil-
laris (arrows) . In this area there is a
small serous RPE detachment (as-
terisk) (hematoxylin and eosin, X
650) . [Published with permission
from the American Journal of Ophthal-
mology 87.698-702, 1979 . Copyright
by the Ophthalmic Publishing
Company.]
OCULAR AND ORBITAL INVOLVEMENT IN LEUKEMIA 219

Fig . 13 . E .P . 43271 . Fluorescein angiogram from the same

patient shown in Fig . 11, showing myriad diffuse leakage
points at the level of the RPE . [Published with permission
from the American Journal of Ophthalmology 87 .698-702,
Fig . 12. E .P . 50048 . This 84-year-old woman had a clini- 1979 . Copyright by the Ophthalmic Publishing
cal diagnosis of anemia and Waldenstrom's mac- Company .]
roglobulinemia . Leukemia was not suspected clinically,
and an autopsy was not done . Examination of the eyes
postmortem showed diffuse choroidal infiltrates of leuke-
mic cells . Cystoid macular edema involving the outer
plexiform layer is present (as(erisk) and associated with
irregularities of the RPE and a diffuse choroidal infiltrate
(arrow) . A thin epiretinal membrane (arrowhead) is
present (periodic acid-Schil ; x 105) .

sometimes it occurs in acute myeloblastic leuke-

mia . 50 CNS leukemia can also occur in adults, but it
is less common ."
Symptoms of CNS leukemia include nausea,
vomiting, lethargy, and seizures .9 ' Eye symptoms
include blurring of vision and diplopia, occurring
with extraocular muscle palsies from involvement of
the cranial nerves ." CNS leukemia may also present
as an asymptomatic papilledema ." Radiation treat-
ments and intrathecal methotrexate are now rou-
Fig . 14 . E .P . 53044 . This 10-year-old girl had a history of
tinely given prophylactically to children with acute
acute lymphoblastic leukemia and was in her fourth CNS
lymphocytic leukemia .""' Even if the therapy is giv- relapse when she presented with a red right eye and a
en after clinical symptoms appear, rapid objective small hypopyon . Anterior chamber tap disclosed atypical
and subjective improvement may occur ."' Leuke- lymphocytes with irregular cytoplasm, indented nuclei,
mia can present as the CNS form, and may require a and prominent nucleoli (modified Papanicolaou stain, x
high index of clinical suspicion for diagnosis .* 1650) . [Published with permission from Retina 1 : 121-149,
On histopathologic examination, the cerebrum, 1981 . Copyright by J .B . Lippincott Co .]
brainstem, and meninges show diffuse or focal inva-
sion by the leukemic cells, often in a perivascular
configuration ."' Sometimes there is discrete tumor retrolaminar leukemic invasion ; or by passive swell-
formation, demonstrable on angiography as well as ing secondary to increased intracranial pressure . El-
postmortem .' "" lis and Little" found optic nerve involvement to be a
Optic nerve involvement may be an extension of feature mainly of acute leukemia . In our series, pa-
CNS involvement, either by direct infiltration of the tients with acute leukemia were only slightly more
nerve head, in which case the intracranial pressure likely to have some type of optic nerve involvement
may he normal ;" or by passive swelling because of (18% of cases, or 43 of 233 eyes) as compared to


2 20 Surv Ophthalmol 27 (4) January-February 1983 KINCAID, GREEN

Fig . 15. This 35-year-old woman

had a flu-like illness three weeks be-
fore death . Postmortem, massive
visceral leukemic involvement was
found, but the brain was normal .
Both eyes show infiltration of the
trabecular meshwork wall of
Schlemm's canal (arrows) and out-
flow channels (arrowhead) by leu-
kemic cells (hematoxylin and eosin,
x 135) .

those with chronic types (16% of cases, or 15 or 97

eyes) .
By fluorescein angiography, the optic disc vessels
in papilledema show heightened permeability, with
early fluorescence and late staining ." Visual acuity
is variable, but usually decreased . Massive direct
infiltration of the optic nerve head by leukemic cells
can give rise to a clinical picture identical to that of
papilledema .
Clinically, papilledema and direct optic nerve
head infiltration may sometimes be differentiated
by the typical retinal perivascular infiltrate seen in
the latter (Fig . 16) . Vision may remain good, de-
spite direct leukemic invasion of the optic nerve
head, although vision is more likely to drop if the
retrolaminar portion of the optic nerve is involved ." Fig . 16. Leukemic infiltrate of the optic nerve head of the
For this reason, it can be difficult to differentiate left eye in a 9-year-old girl with ALL . The infiltrate ex-
papilledema (passive swelling) from direct invasion, tends around the retinal vessels (arrows) . (Photograph
and indeed they may coexist ." Examination of the courtesy of William E . Newby, M .D .)
spinal fluid for leukemic cells will enable the clini-
cian to determine the presence ofCNS leukemia and
hence papilledema, but this does not imply the pres-
ence or absence of direct optic nerve invasion . 87 was more common in acute leukemia (Figs . 17 and
Optic nerve involvement by papilledema shows 18) . Infiltration of the optic nerve head, mainly in a
the typical histologic picture, with diffuse cytoid perivascular pattern (Figs . 17 and 18), occurred in
bodies and small areas of hemorrhage . Rarely, there 14 patients in our series, but in none was it massive .
may be focal necrosis .' There may also be direct Ellis and Little" reported a patient with chronic
infiltration by leukemic cells, either in a retrolam- myelogenous leukemia who had been treated with
inar location, or in the optic nerve head, or both . intrathecal methotrexate; the infiltrate of tumor
Optic nerve head infiltration sometimes extends to cells was present only distal to the termination of the
contiguous retina ." arachnoid sheath, 2 to 3 mm posterior to the disc .
In our series, 37 of the 384 patients had infiltra- This indicates that the intraocular portion of the
tion of retrolaminar optic nerve and meninges ; this optic nerve is beyond the reach of intrathecal che-
OCULAR AND ORBITAL INVOLVEMENT IN LEUKEMIA 221

Fig . 17 . E .P . 32542 . A 19-month-old

boy had had AML diagnosed at age
8 months . Autopsy disclosed diffuse
CNS infiltration . Top : The optic
nerve in cross section shows diffuse
leukemic infiltration along the fibro-
vascular pial septa (arrows) and
strikingly around the central artery
and vein (arrowheads) . Bottom :
The optic nerve head shows leuke-
mic infiltration mainly in a perivas-
cular location (arrows) . There is
mild peripapillary crowding (aster-
isk) and elevation of the nerve head
(hematoxylin and eosin ; A, x 65 ; B,
x 35) .

motherapy, and should be locally irradiated when
involved .
E. ORBIT
All types of leukemia may involve the orbit ; how-
ever, orbital involvement is more common in acute
leukemia than in chronic, and it occurs more often
in the lymphoid type than in the myeloid type .`" In
our series, orbital infiltration was more common in
chronic leukemia, with 14% of eyes (14 of 97 cases)
showing involvement, versus 7 .3% in acute leuke-
mia (17 of 233 cases) . We found 8% (16 of 201)
orbital involvement in myeloid leukemia and 12%
(15 of 125) in lymphoid leukemia . Most of these
cases, however, showed a mild diffuse infiltrate,
rather than massive tumor formation .
Orbital infiltration in leukemia presents with ex-
ophthalmos, lid edema and chemosis, with


222 Surv Ophthalmol 27 (4) January-February 1983 KINCAID, GREEN

Fig . 18. E .P . 375 . This is the same

patient as is shown in Fig . 4 . The
optic nerve is seen in longitudinal
section (asterisk), with intradural
(arrows) and subdural (arrow-
heads) infiltration by leukemic cells
(hematoxylin and eosin, x 130) .

pain . M0,13 Orbital biopsy may be necessary, espe-

cially when the underlying systemic disease pre-
sents first in the orbit and is otherwise unsuspected"
(Figs . 19 and 20) .
The orbital mass of cells formed in myeloid leuke-
mia has been called a chloroma, or granulocytic
sarcoma . The green color, which is not always pres-
ent, is caused by the enzyme myeloperoxidase .
Myeloid leukemia may present with an orbital
chloroma,'01 and it is an ominous sign ; in two se-
ries 16,63 with a total of 56 children with orbital chlo-
romas, death occurred within 18 months . The tu-
mor can erode into the cranial cavity . Treatment
consists of chemotherapy for the underlying leuke-
mic process ."
On histopathologic examination of orbital granu- Fig . 19 . E.P . 48582 . At the time oforbital biopsy ofthis 63-
locytic sarcoma, the cells appear similar to reticu- year-old white man with orbital masses, the ophthalmol-
lum cells . The nuclei are more oval, however, with ogist was unaware of the diagnosis of CLL, and believed
vesicular nucleoplasm and less well-defined nu- the lesion was a pseudotumor . Sheets of well-differentiat-
cleoli . In young patients diagnosed as having reticu- ed lymphocytes that have infiltrated muscle are present in
lum cell sarcoma ("histiocytic" lymphoma), it is the biopsy specimen (hematoxylin and eosin, x 200) .
more likely that they actually have granulocytic
sarcoma . 52
The analogous orbital tumor in lymphoid leuke-
mia is a lymphosarcoma . The tumor is classified by Eight of the 384 cases in our autopsy series showed
cell type and by whether it is diffuse or nodular . Any lacrimal gland infiltration (Fig . 21) . Since the lacri-
type of lymphoma may progress to lymphatic leuke- mal gland was not routinely recovered at autopsy,
mia, but lymphocytic lymphoma is the most com- the true prevalence of involvement is doubtless
mon . Reticulum cell sarcoma ("histiocytic" lym- higher . Biopsy of lacrimal gland and orbit led to the
phoma) is least likely to lead to leukemia . diagnosis of leukemia in one patient in our files (Fig .
Specific orbital structures, such as the lacrimal 22) .
gland, may also be infiltrated by leukemic cells . Rarely, the extraocular muscles may be infiltrated
OCULAR AND ORBITAL INVOLVEMENT IN LEUKEMIA 223

Fig . 20. E .P . 10050 . A 28-year-old

white woman presented with firm,
nontender, swollen upper lids for 10
days . A diagnosis of lymphocytic
leukemia was made from the blood
picture and the orbital biopsy . This
shows sheets of lymphocytes, with
nuclei of somewhat varying size (pe-
riodic acid-Schiff, x 400) .

Fig . 22 . E .P. 10050 . This is from the same patient as Fig . 21 . E .P . 41178 . This is from the same patient as
shown in Fig . 19 and shows a diffuse cellular infiltrate shown in Fig . 14. The lacrimal gland shows a diffuse
around ducts (asterisks) of the lacrimal gland (periodic infiltrate of leukemic cells between acini (arrows) and
acid-Schiff, x 525) . around ducts (hematoxylin and eosin, x 65) .

by leukemic cells . To our knowledge, this has not
been evident clinically as an isolated muscle palsy,
but extraocular muscle involvement was present in
five cases in our autopsy series, including one case
with massive infiltration (Fig . 23) . Leukemic infil-
tration may extend into the sinuses, simulating
sinusitis n
F. CORNEA AND SCLERA
Because the cornea is normally avascular, direct
invasion by leukemic cells would not be expected . In
Allen and Straatsma's series,' there was no corneal
involvement beyond limhal infiltration ..
However, leukemia can induce formation of a
sterile ring ulcer with iritis and pannus . 9 In one


224 Surv Ophthalmol 27 (4) January-February 1983 KINCAID, GREEN

E .P, 375 . This is from the
Fig . 23 .
same patient as shown in Figs . 4 and
17 . Muscle fibers (arrows) are sepa-
rated by a marked infiltrate ofleuke-
mic cells (hematoxylin and eosin, x
125) .

patient, the diagnosis of AML was made during

work-up for bilateral corneal ring ulcers (Fig . 24) .
The ulcers resolved after a month of topical genta-
micin, atropine and steroids, along with systemic
chemotherapy for AML ."
Bhadresa 9 reported a patient who presented with
a corneal ring ulcer with limbal stromal infiltrates .
On bone marrow examination, a diagnosis of acute
myeloblastic leukemia was made . The patient died
before treatment could be effective, and diffuse an-
terior chamber involvement was found at autopsy .
Also, peripheral corneal ulceration has been re-
ported in a patient with leukemia and herpes zoster
ophthalmicus ."
In recent years, in postmortem eyes we have seen

SP17-16342 . A 53-year-old woman had had red

Fig . 24 .
eyes with decreased vision for one week, and was found to
have a peripheral ring ulcer present in both eyes (top) .
She failed to improve on antibiotic therapy, and when she
returned two days later she had a fever, palpable lymph
nodes, and an elevated white count . A scraping of the
ulcer and a bone-marrow biopsy (bottom) showed imma-
ture mononuclear cells (hematoxylin and eosin, x 400) .
A diagnosis ofAML was made and chemotherapy begun .
Two weeks later, the ulcers had resolved . [Published with
permission from the American Journal of Ophthalmology
76:69-72, 1973 . Copyright by the Ophthalmic Publishing
Company .]
OCULAR AND ORBITAL INVOLVEMENT IN LEUKEMIA
Fig . 25. E . P . 45841 . This 39-year-old man developed
headaches, chest pain, and leukopenia, and a bone-mar-
row aspiration led to the diagnosis ofAML . Therapy with
cytosine arabinoside, daunoruhicin, and allopurinol was
begun, but he died a month later . The corneal epithelium
is thinned to 2 to 3 cell layers, shows intracellular edema,
hyperchromatism and mild nuclear pleomorphism (he-
matoxvlin and eosin, x 500) .
corneal epithelial changes which we have attributed
to chemotherapy . These changes included thinning,
irregularity, faulty maturation, and keratinization
and were present in eight patients from our series ;
all were cases from within the past five years
(Fig . 25),
Scleral infiltration is usually a finding at autopsy,
and usually occurs in acute leukemia . The cells are
most often found in the episclera, in a perivascular
location .' In our series, 50 of 357 patients (14%)
had episcleral or scleral involvement, in a generally
perivascular location, either anteriorly or posterior-
ly . This finding was equally common in acute and
chronic leukemia . Another patient had an eye enu-
cleated because of a clinical picture of uveitis ; the
eye showed marked episc :Ieral infiltration (Fig . 26) .
G . CONJUNCTIVA
Conjunctival involvement occurs most often in
patients with lymphocytic leukemia .'9 Cellular in-
vasion is found at all levels of the substantia propria,
and can be diffuse or patchy, tending to concentrate
along blood vessels .' One patient with CML was
found to have comma-shaped venular abnormalities
previously believed to be pathognomonic of the sick-
le cell hemoglobinopathies . The authors believe the
vascular changes to be secondary to hyper-
viscosity ."'
225
Fig . 26. E .P . 40886 . A 63-year-old woman was diagnosed
as having CLL . After systemic prednisone was tapered,
she developed a uveitis-like picture, with elevated pres-
sure in the right eye . When medication would not control
the ocular pain and vision became no light perception, the
eye was enucleated- There is a marked thickening and
infiltration of the episclera (between arrows) . the sclera
(asterisk) is normal and a mild leukemic infiltrate is pre-
sent in the choroid (arrowhead) (hematoxvlin and eosin,
x 55) .
iwo cases have been reported in which acute
lymphoblastic leukemia presented with conjuncti-
val involvement . In one .'-" the nodule was solitary
and small, with localized injection, resembling an
episcleritis . Vision was normal. In the other pa-
tient,'' infiltration was much more diffuse and mas-
sive, producing limited motility in both eyes . In
both of these patients, the involved area was firm
and nontender .
Another patient"" presented with firm nontender
infiltrates of the conjunctiva of both eyes, with limi-
tation of motility . On biopsy, undifferentiated blast
cells were found, leading to a diagnosis of atypical
lymphatic leukemia .
Four patients at our institution underwent biopsy
for conjunctival swelling or masses . In one, the diag-
nosis of leukemia was not suspected prior to the
biopsy (Fig. 27) . The others were known to have
leukemia which was being treated .
In our autopsy series, 14 patients (4%) showed
some degree of leukemic conjunctival infiltration,
often with subconjunctival hemorrhage . This figure
is artificially low, because the ocular specimens ob-
tained prior to 1965 included only the posterior
poles .
2 26 Surv Ophthalmol 27 (4) January-February 1983
Fig . 27. E .P. 47018 . A 72-year-old white woman devel-
oped a lohulated, firm grayish mass of the conjunctiva
near the left lateral rectus which was biopsied . Sheets of
mature-appearing lymphocytes were seen, and further
work-up led to the diagnosis of lymphocytic leukemia
(hematoxylin and eosin, X 310) .
H . OTHER OCULAR MANIFESTATIONS
Some less common manifestations of ocular leu-
kemia include anterior segment necrosis, dacryocys-
titis, and skin infiltration . Anterior segment necrosis
classically occurs after multiple rectus muscle inser-
tion operations, because the course of the anterior
ciliary arteries is interrupted . Persons with blood
diseases such as sickle cell disease are more vulner-
able, presumably because of decreased oxygenation
and increased viscosity . Leukemia can also cause
anterior segment necrosis, due either to hyper-
viscosity or anemia .
A patient with CLI5 1 who had a recess-resect
muscle operation for strabismus developed iritis,
conjunctival edema, and folds in Descemet's mem-
brane postoperatively, with decreased vision but
normal intraocular pressure . She was known to
have a hemoglobin of 13 .3 gm/dl . With topical ster-
oids, the inflammation gradually resolved, leaving
sector iris atrophy .
Another patient22 developed spontaneous anteri-
or segment ischemia . He had chronic myelocytic
leukemia with a white cell count of 256,000/cu mm .
The inflammation resolved after topical steroids
and radiation therapy .
Another unusual manifestation of leukemia is da-
cryocystitis ." A patient with ALL, controlled on
chemotherapy, developed lacrimal duct obstruc-
tion . On dacryocystorhinostomy, the excised mate-
rial consisted of sheets of lymphocytes with a mini-
KINCAID, GREEN
Fig . 28 . E .P . 44384. A 69-year-old man with bilateral
recurrent dacryocystitis was admitted for dacryocysto-
rhinostomies, but was found to have CLL . Tissue ob-
tained at the time of surgery shows a diffuse infiltrate of
mature lymphocytes in the substantia propria of the nasal
mucosa . Overlying epithelium (arrow) appears unremar-
kable (hcmatoxylin and eosin, x 170) .
mal amount of connective tissue .
A similar patient presented at the Wilmer Insti-
tute with bilateral dacryocystitis and was discov-
ered on medical work-up to have CLL . Dacryocys-
torhinostomies were performed, and lymphoid
tissue was found to have infiltrated the nasal muco-
sa bilaterally (Fig . 28) .
Leukemia uncommonly infiltrates the dermis .b' A
4-year-old child with known acute blastic leukemia
presented with diffuse lid swelling of both eyes . The
right lower lid was biopsied, and this revealed undif-
ferentiated blast cells (Fig . 29) .
I . OPPORTUNISTIC INFECTIONS
Leukemics are susceptible to a wide variety of
infections by organisms that are considered to he
saprophytic . These can include viral, fungal, proto-
zoan, and bacterial infections .YO Because patients
with leukemia are immunosuppressed, both as a
result of their disease and from chemotherapy, they
are more susceptible to such infections .
One of the most common viral agents in leukemic
infection is cytomegalovirus . In normal persons the
virus causes mild mononucleosis-like symptoms, if
any, but in an immunosuppressed host there may be
considerable involvement in neuroectodermal tis-
sue ." The virus invades the retina causing necrosis,
vessel sheathing, hemorrhage 12 and combined exu-
dative and rhegmatogenous retinal detachments ."
OCULAR AND ORBITAL INVOLVEMENT IN
Fig . 29 . E .P . 39055 . Top : A 4-year-old girl with acute
blastic leukemia previously treated with chemotherapy
presented with a firm mass of the right lower lid . Bottom :
biopsy specimen shows sheets of blast cells with variable-
sized nuclei (hematoxylin and eosin, x 500) .
Visual loss may be severe if the lesions arc near the
macula, but can he slight if the lesions are peripher-
al . The retinal lesions may resolve over a period of
weeks or months ." The pigment epithelium is in-
volved, but the choroid is spared and it often shows
little inflammatory response ." The fundus appear-
ance can simulate leukemic infiltrates . In one pa-
tient," chorioretinal biopsy of the blind eye was
used to differentiate between reactivation of leuke-
mia and cvtomegalovirus retinitis, for which the
therapeutic regimens are different .
Other viruses, such as herpes simplex, herpes zos-
ter, and measles virus, may cause a necrotizing ret-
initis in the immunocompromised host ." In patients
with immune deficiencies, such as leukemia or de-
bilitating diseases, herpes zoster also may cause a
peripheral corneal ulcer," in contrast to the usual
presentation of dendritic ulcer or punctatc keratitis
with herpes zoster .
Mumps virus has been reported as causing an-
terior granulomatous uveitis in a child with acute
LEUKEMIA 227
Fig . 30. E .P . 40937 . A 16-year-old white girl was found to
have AML and died of Candida sepsis five years later .
Candida organisms were cultured from the FNS . Foci of
fungi (asterisk) without an inflammatory reaction are in
the choroid (periodic acid-Schiff, x 200) .
lymphoblastic leukemia in remission . Mumps virus
was isolated from the throat, and the uveitis cleared
on mydriatic therapy alone .'
Fungi are common causes of ocular infections in
leukemics . Candida infection causes uveitis and ret-
initis, often with characteristic fungus balls in the
vitreous . If the lesions are near the macula, visual
acuity may be much reduced ." , " Often there is dif-
fuse ocular candidiasis . 2° 7° Histopathologically, foci
of budding yeast forms and pseudohyphae are seen
in the uveal tract, retina, or vitreous""' (Fig. 30) .
Depending on the amount of bone marrow reserve
following therapy, these fungal lesions may or may
not have an inflammatory cell component .
Aspergillus is also a rather common cause of fun-
gal infection, also producing a choroiditis and vitri-
tis . 21 ' Other opportunistic organisms involving the
eye include Mucor, Cryptococcus, and Toxo-
plasma, 2U and also bacteria (Fig . 31) .
J . THERAPY OF OCULAR INVOLVEMENT
Advancements in the treatment of leukemia, es-
pecially ALL, in recent years have been little short
of amazing . Nevertheless, morbidity from leukemia
can still he a difficult management problem .
To our knowledge, there has been no systematic
attempt to formulate treatment protocols for ocular
involvement in the leukemias, although there have
been numerous case reports and small series de-
scribing treatment .
Certain manifestations, such as conjunctival infil-
tration, respond well to systemic chemotherapy ."

22 8 Surv Ophthalmol 27 (4) January-February 1983
Fig . 31 . E .P . 43502 . An 18-year-old girl had ALL and died of gram-negative sepsis . Left : A low-power view of the retina
shows an area of retinal necrosis (asterisk) . The underlying choroid is normal . Right: At higher power, gram-negative
rods are visible within inner retina (Brown and Hopps ; A, x 210 ; B, x 2000) .
However, the eye is part of the central nervous sys-
tem, and as such, is a pharmacologic "sanctuary,"
which may not be treated adequately by drugs given
systemically . 85
Prophylaxis for CNS leukemia consisting of in-
trathecal methotrexate and radiation to the head
and spine is now routinely given for children with
ALL,', " but, as Ellis and Little 34 demonstrated, the
eye is beyond the reach of chemotherapeutic agents
injected intrathecally . Ridgway and coworkers" ad-
vocated prophylactic irradiation to the eyes as well
as the brain, but were unable to suggest a dose .
We have found no reports describing prophylac-
tic radiation given to the eyes or orbits, Radiation
has been given, in widely varying dosages and
schedules, for leukemic infiltration of the eye, both
anteriorly and posteriorly, and the orbit . Newman
and coworkers 76 stated that 800 rads is effective as
local therapy in 90% of patients, but did not give
details in their series .
Local irradiation, along with systemic chemo-
therapy for the underlying disease, can help resolve
iris infiltration, pseudohypopyon, and accompany-
ing elevated intraocular pressure . ,?sua8,74,n,bou Mar-
tinfi 7 used 500 rads during a six-day period, and
Masera and coworkers" used 390 rads during a 22-
day period, to induce clinical resolution . Fonken
and Ellis 37 used an even lower dose, 250 rads over
five days, to treat iris infiltration, glaucoma, and
leukemic retinopathy . Clinically, they were success-
ful, but the eyes obtained postmortem two months
KINCAID, GREEN
later contained leukemic infiltrates throughout, es-
pecially posteriorly .
Subconjunctival steroid injection" and intrathe-
cal methotrexate45 have also been reported to be
helpful for iris infiltration and secondary glaucoma ;
however, Mark and coworkers" found no response
to local steroids .
Decreased vision from leukemic infiltration of the
optic nerve is an ophthalmic emergency .' Ridgway
et al" advocate 1000 rads over 5 days ; other au-
thorsssss,74,H7 have used doses from 700 rads5 to 2000
rads A7 with success . Rosenthal and associates 87
pointed out that papilledema and direct optic nerve
involvement may look similar and may coexist ; ex-
amination of the spinal fluid is needed to diagnose
CNS leukemia . These authors" also noted that in-
vasion of the retrobulbar optic nerve is much more
devastating visually than leukemic invasion at the
disc.
Orbital involvement by AML (granulocytic sar-
coma) 'o and ALL (lymphoblastoma) 73 :8' carries a
very poor prognosis despite radiation and chemo-
therapy . Quite evidently, it is possible to treat ocu-
lar manifestations of leukemia successfully, but
there is as yet no standardized protocol, nor has the
use of prophylactic radiation to the eyes and orbit
been adequately addressed to date .
K. DRUG TOXICITY
Many cytotoxic drugs have been developed for
the treatment of leukemia and other cancers, and it
OCULAR AND ORBITAL INVOLVEMENT IN LEUKEMIA 229

is not surprising that these drugs can also be toxic to

normal cells . Some have been identified as being
especially toxic to ocular or CNS tissues .
Busulfan was reported to cause cataracts in a to-
tal of 15 patients of 44 studied ." ," These cataracts
are usually posterior subcapsular, 80 and they may
occur in persons as young as 23 years ."
Vincristine and vinblastine are toxic to the CNS,
and have been clinically shown to affect the motor
nerves to the eye (nerves III, IV, VI, VII) and also
to induce corneal hypesthesia (nerve V) . 2 Green 41
has shown experimentally that primates are exquis-
itely sensitive to vincristine and has observed dis-
ruption of neurotubules and optic atrophy .
Fig . 32. E .P . 51557 . A 41-year-old white woman, with
Nitrogen mustards have in the past been injected
AML in remission, received a bone-marrow transplant
intra-arterially for perfusion of intracranial malig-
from an HLA-identical brother . She died seven weeks
nancies . In three patients, severe uveitis developed later with GVHD and sepsis . The corneal epithelium is
in the ipsilateral eye . In one eye examined postmor- flattened, with disorderly maturation and early keratini-
tem, a necrotizing vasculitis was present .' In rab- zation (hematoxylin and eosin, x 320) .
bits, topically applied nitrogen mustard raises the
intraocular pressure," but this has not been shown
to occur after systemic administration . Intravitreal
injection in rabbits causes anterior segment flare, lial opacities and microcysts . A corneal biopsy was
vitreous membrane formation, and retinal performed on one eye, which showed degeneration
hemorrhages ." of cells within the basal layer .
Cytosine arabinoside has recently been shown to
be toxic to the corneal epithelium when given sys-
L BONE MARROW TRANSPLANT AND GRAFT-
temically, and also when topically applied . Hopen
VERSUS-HOST DISEASE
and coworkers" described three patients with mye-
logenous leukemia who developed symptoms of for- A recent advance in treatment of leukemia, and
eign body sensation and blurred vision while on also aplastic anemia and certain other disorders, is
cytosine arabinoside . Clinically, there were epithe- the bone marrow transplant . After the patient's

Fig . 33 . E .P . 50062 . A 23-year-old

woman, with A MI. i n remission, re-
ceived a bone-marrow transplant
and died five weeks later . Autopsy
revealed GVH disease with skin,
gastrointestinal tract, and salivary
gland involvement . The lacrimal
gland shows distension of the acinar
epithelium by a periodic acid-Schiff
positive material and marked nar-
rowing of the acinar lumina (period-
ic acid-Schiff, x 625) .
23 0 Surv Ophthalmol 27 (4) January-February 1983
marrow is completely destroyed by irradiation and
chemotherapy, a transplant from the bone marrow
of an HLA-compatible sibling is performed . Ideally,
these normal cells proliferate, giving the host nor-
mal red cell, white cell, and platelet function .
Two serious complications may arise . Despite ap-
parently adequate pretreatment, the leukemic cell
line may recur, requiring further chemotherapy ."
In some cases, leukemic transformation has been
proven to occur in the grafted cells ."
In addition, because the implanted lymphocytes
are immunocompetent, and because our present
ability to detect immunocompatibility is imperfect,
the risk of acute and chronic graft-versus-host dis-
ease is very real . The transplanted white cells recog-
nize the host as foreign, and attack host tissue .
Acute graft-versus-host disease (GVHD) manifes-
tations include fever, skin rash, dry mouth, enteritis,
and hepatitis . Chronic GVHD presents as a Sjo-
gren's or scleroderma-like illness ."
Ocular manifestations of GVHD include dry
eyes, pseudomembranous conjunctivitis, ectropion
of the lid, and uveitis . The patient's sensation of dry
eyes can be verified by the Schirmer test . In severe
cases the cornea may undergo keratinization .
On histopathologic examination, the cornea and
conjunctiva in graft-versus-host disease show thin-
ning (Fig . 32) and, in more severe cases, keratiniza-
tion . The lacrimal gland shows flattening of the
acini and inspissation of eosinophilic periodic-acid-
Schif -positive material in the tear ducts, and also
within the secretory cells (Fig . 33) (Jabs DA, Hirst
KINCAID, GREEN
Fig . 34. E .P . 45261 . A 17-year-old
white boy was diagnosed as having
ALL with CNS involvement . Four
years later he was admitted for
bone-marrow transplant from an
HLA-identical sibling. He died six
weeks after the transplant . Postmor-
tem bone-marrow examination
showed no leukemic cells . Large
cells with abundant eosinophilic cy-
toplasm (arrows) are present in the
choroid . Similar cells are also pre-
sent within some choroidal blood
vessels . The overlying RPE is intact
(hematoxylin and eosin, x 450) .
LW, Green WR, Tutschka PJ, Santos GW, Be-
schorner WE, personal communication, 1981) . The
choroid contains unusual-appearing histiocytes
with granular, densely eosinophilic cytoplasm
(Fig . 34) .
III . Conclusion
The leukemias can cause numerous intraocular
and extraocular changes . Although some of these
are rare, they can still be of prognostic significance .
All of the main manifestations of leukemic involve-
ment can be explained on the basis of anemia and
hypoxia, blood hyperviscosity, compression by
masses of cells, or direct tumor infiltration . Various
other effects occur from superinfection or from
therapeutic procedures, such as radiation, chemo-
therapy, or bone marrow transplant .
Acknowledgments
We thank Dr . Rein Saral for review of the manuscript
and Mr . James David Andrews and Ms . Marcia Kelley
for assistance during preparation of the manuscript .
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Outline
I . Systemic leukemia and classification
II . Ocular involvement : Methods, results, and review
A. Retina
B . Choroid
C. Iris and anterior segment
D. Optic nerve and central nervous system
E. Orbit
F. Cornea and sclera
G. Conjunctiva
H. Other ocular manifestations
I. Opportunistic infections
J. Therapy of ocular involvement
K. Drug toxicity
L. Bone marrow transplant and graft-versus-host
disease
III . Conclusion
Supported in part by a Heed Fellowship (Dr . Kincaid) and re-
search grant I R01-EY01804, National Eye Institute (Dr. Green) .
Dr. Kincaid is currently Assistant Professor of Ophthalmology and
Pathology at the University of Texas in San Antonio .
Reprint requests should be addressed to W . Richard Green,
M .D ., Eye Pathology Laboratory, Wilmer Institute, Johns Hopkins
Hospital, 600 N . Wolfe St ., Baltimore, MD 21205 .