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Immunohistologic
Features
Predict
Clinical
Lymphoid
By L. Jeffrey
The
natural
history
conjunctiva
histologic
of lymphoid
were
evaluated
conjunctival
lymphoid
lesions
localized
to
histologic
lymphoma
classified
as benign
pseudotumor).
of
which
could
sion
be
immunoglobulin
reduced
survival
sion
for
(P <
(P <
also
correlated
L
monomorphous
phomas,
and
small,
classify
or
using
their
histologic
the
regarding
clinical
designation
atypical
indeterminate,57
be
globulin
expression
found
correlate
pattern
thus
has led
to
histologi-
they
of
of disease
investigators4’2’4
In
and
Jakobie&2
orbital
and
conjunctival
with
equal
that
have
expression
behavior.
Knowles
emphasized
frequency,
the
to
largest
found
ies
including
negative),
to
monotypic
clinical
Blood,
localized
immunoglobulin
lymphocytic
addition,
44
determine
features
we
and
lesions
expression,
indeterminate)
have
the
Vol 74. No
assessed
prognostic
parameters
6 (November
1), 1989:
in these
staging
one
of
risk
lymphoid
relationship
atypia
with
an indolent
polytypic
& Stratton,
Mono-
lymphomas
and
of
with
dissemina-
cytologic
malignant
remains
of
infiltrates.
without
of dissemination
locally
monotypic
correlates
increased
B-cell
lesion
Thus.
significantly
infiltrates
to lymphoma
have
December
been
small
a
clinical
lymphocytic
to be determined.
Inc.
accessioned
the
on
in the
orbital
and
were
patients,
two
of
biopsy
diagnosis
(slides
not
node (1),
logic
lung
cases
without
studies.
(1)
the study
all
Malignant
as defined
by Jakobiec
follicular
with
be indeterminate
using
indeterminate
cells
and
follicular
review
the
additional
had
a previous
a
pseudolymphoma
gland
from
(2),
analysis
as malignant,
were
defined
one
could
were
alone.
biopsy
results,
Also
of
included
of
follicular
using
all
of
to
in the
small
and
hyperplasia
histologic
lesions
small
considered
composed
not be made
were
pseudotumor
composed
atypia
between
immunologic
cases
inflammatory
criteria
or
immunohisto-
as monomorphous
Infiltrates
tiny
benign,
of the
Benign
et al’3;
distinction
lymphoma
of the
Eight
excluded
results
or no cytologic
was
in which
had
lymphocytic
parotid
lymphocytes.’2’5
histologic
group
large
also
of the
hyperplasia.
minimal
or
(4),
classified
lesions
two
reactive
analysis.
orbit
were
knowledge
atypical
lymphocytes
and
patients
chronic
group.
of clearly
and
Nineteen
syndrome,
the
were
infiltrates
types
88
study
hyperplasia
involving
61 patients,
of
we collected
further
lymphoid
and
Laboratories
this
or
Sjogren’s
infiltrates
Pathology
1987.
from
had
studies
lymphoid
lymphoma
excluded
of
For
December
whom
available)
indeterminate
Wright
Hospital.
extraorbital
leukemia
immunohistologic
conjunctival
Homer
through
prior
METHODS
section
and
General
accessioned
of
frozen
James
Massachusetts
history
AND
1980
done
From
the Departments
Therapy.
studof
in small
infiltrates.
In
significance
of
cases.
pp 2121-2129
likelihood
criteria.
that
expressed
and
Radiation
that
cannot
significance
particularly
(histologically
histologic
(all
prognostic
the
infil-
expression
lymphoid
be used to predict
subsequent
clinical
behavior.
In this study we report
the follow-up
of 61 patients
with
lymphoid
infiltrates
that initially
presented
in the orbit or
conjunctiva,
localized
.005)
although
conjunctival
grade
by Grune
After
approximately
immunologic
The
lymph
infiltrates
express
be considered
to
immunoglobulin
clinical
and
risk
course.
Iymphoma.
and
lymphocytic
as do low
leaving
proportion
date,
disseminate
and
by orbital
small
as
later
expression
patient
Histologically,
dissemination
other
the
increased
(P <
disseminated.
months
survival
cases
to
lymphocytic
polytypic
to
and
infiltrates
of
subsequent
reported
with
In contrast,
the
with
monotypic
30%,
correlated
ofdiagnosis.
series
or
of
presumed
to be low grade because of
of cytologic
atypia.
In a small
series of cases
reported
from
this hospital,5
monotypic
immuno-
lack
not
lym-
lymphomas,
previously
at time
could
an
cases
MATERIALS
proliferations,8
lymphocytic
and
44
reduced
Since
Uncertainty
a high
of
immunoglobulin
with
all
immunoglobulin
“
that
30
a 1989
admixed
infiltrates,4
have
recurred
infiltrates
difficult
lesions
analysis
monotypic
infil-
without
as atypical
shown
small
of dis-
L. Harris
Separate
that
for
significant
expres-
hyperplasia
composed
are
Conjunctival
and for the 22
histologically
indeterminate
lesions
(P = .06). For the localized small
lymphocytic
infiltrates.
monotypic
immunoglobulin
expression
conferred
a 50% risk of dissemination.
In contrast.
no patients
with polytypic
small lymphocytic
and conjuncthree groups:
lymphocytic
immunoglobulin,
B cell
their
of these
studies
have
and conjunctival
monotypic
alone.’”
small
with
malignant
and benign
studies8
orbital
criteria
lymphocytic
pseudolymphoma,9’#{176}
Recent
or
which
and
Nancy
correlated
behave
dissemination
orbit
into
centers,
behavior
in prior
hyperplasia,3
cally
with
germinal
of
follicular
infiltrates
lymphocytes
cells
all cases.
and
.05).
dissemination
typic
lymphocytic)
atypical
reactive
and
pseudotumor,
nonatypical
plasma
cytologically
benign
clearly
inflammatory
risk
showed
tion
were
likelihood
(small
(P <
trates
on expres-
immunoglobulin
of the
histologically
INFILTRATES
be divided
may
or
correlated
increased
trates
cases
For
increased
indeterminate
YMPHOID
tiva
lymphoma.
and
with
all histologically
of these
expression
.05)
benign
Based
20
). Monotypic
.001
atypia.
as
indeterminate).
monotypic
infil-
cytologic
M. Linggood,
infiltrates
dense
classified
lymphocytic
as
were
or inflammatory
were
without
immunoglobulin.
as small
classified
Rita
significantly
and
14 cases
(44%)
confidently
reclassified
and
orbital
were
hyperplasia
infiltrates
(histologically
orbit
44 patients
with
or conjunctivae.
atypical).
lymphocytes
of monotypic
with
infiltrates
(follicular
27
not
semination
patients
(cytologically
small
malignant
61
20
C. Harmon,
of the
of Orbital
Infiltrates
To determine
if immunoclinical
outcome.
these
infiltrates.
including
one
or both
orbits
and
trates
in
criteria.
malignant
David
infiltrates
is poorly understood.
features
could
predict
features
Using
Medeiros,
Behavior
Submitted
General
February
Address
reprint
of Pathology,
tute,
of Pathology,
Massachusetts
22,
Building
Bethesda,
1989;
requests
MD
JO, Room
publication
costs
ofthis
article
payment.
This
article
must
© I 989
June
MA.
30,
Medeiros.
1989.
MD,
2N I 13, National
Laboratory
Cancer
Insti-
20892.
The
indicate
Boston.
accepted
to L. Jeffrey
charge
“advertisement”
Medicine,
Hospital.
in accordance
with
were
defrayed
therefore
18 U.S.C.
in part
be hereby
section
by page
marked
1 734 solely
this fact.
by Grune
& Stratton.
Inc.
0006-4971/89/7406-040$3.00/0
2121
to
From www.bloodjournal.org by guest on July 31, 2017. For personal use only.
MEDEIROS
2122
monotypic
immunoglobulin
malignant
and
20 of 27 cases
reclassified
as malignant
were
ing to the
Working
(including
that
those
were
that
were
histologically
lymphoma
and
subclassified
or an avidin-biotin
method
All cases were stained
light
and
cases,
heavy
NY,
(kappa,
(Dako
prior
as has been
with antibodies
chains
alpha)
ville,
the
curves
(Gilbert-Gehan)
was
calculated
by a generalized
accord-
Accurate
to I 983,
previously
reactive
lambda,
mu,
Scientific
or Bethesda
were performed
method
(prior
on
to
described.5’6
and
Research
and
Chemical
and
Co, Hicks-
positive).
Bethes-
All
are summarized
were
group
thus
included
classified
and were phenotypically
classified
as benign.
trates
were obviously
benign using histologic
ing nine cases of inflammatory
pseudotumor
physical
examination,
complete
blood
count,
and
chest
radiograph,
and 90% of patients
by orbital computerized
tomography (CT). Approximately
two thirds of patients
underwent
chest
and/or
abdominal
CT scan and bone marrow
biopsy.
A small
minority
of patients
were also studied
by abdominal
lymphangiogram and/or
tissue biopsy. When staging studies revealed
sites of
disease
in addition
to the orbit or conjunctiva,
dissemination
was
considered
to be present
at diagnosis.
Patients
with unilateral
and
bilateral
disease
were considered
to be stage IE. Five of seven
patients
with
bilateral
involvement
underwent
unilateral
logic
and
neither
immunohistologic
8 received
findings:
chemotherapy
(excision
only).
For
26 received
alone,
biopsy
two
patients
radiation
2 both
with
lymphomas
and
without
of
had
polytypic
( 14
lesions
histologically
benign
and
The
had
irradiated
using
inflammatory
patients
received
anterior
and
a diagnosis
external
beam
anterolateral
of orbital
irradiation
overlapping
to 40 Gy
fields
and
who
chemotherapy
Clinical,
with survival
method
received
histologic,
and
and freedom
of Kaplan
and
individualized
The
significance
hyperplasia.
indistinguishable
lymphoma,
expressed
classified
provisionally
composed
of small
polytypic
and large
of
Fourteen
infilcriteria,
includand five exam-
Six
lesions,
small
although
lymphocytic
immunoglobulin
as diffuse
and
hyperplasia.
lymphocytes,
One
grouped
were
biopsy
with
the
because of its small size,
and was classified
as
hyperplasia.
The
which
involved
Table
also
involved
the
conjunctiva.
the
1 . Histologic
Lymphoid
.
Histologic
patients
gland.
of the Orbit
had
Classification
lesions
bilateral
of 61
Combined
Histologic
and
Immunologic
Diagnosis
.
Localized
Cases
All Cases
Monotypic
(20)
F-SCC
(20)
8 (1 3%)
F-MC
F-IC
4
3 (5%)
-
1 (2%)
1
D-SCC5(8%)
D-MC
SNC
(27)
Monotypic
(20)
SLL
2
1 (2%)
D-LC
Indeterminate
-
1 (2%)
1
1 (2%)
20
-
(32%)
15
DH6(10%)
Polytypic(7)
6
FH1(2%)
Benign
(14)
Polytypic
(14)
1
P 9 (14%)
9
FH5(8%)
regimens.
Abbreviations:
mixed
cell;
lymphocytic
sia;
F-. follicular;
LC,
large
lymphoma;
P. inflammatory
in
and Conjunctiva
(no.)
(no.)
Twelve
patients
and Immunologic
Immunoglobulin
Expression
Classification
2) ranged
(Table
lacrimal
Seven
Infiltrates
.
61
a median
age of 67 years. There were
The orbit was involved
in 49 cases, 9
4 mV
of the differences
subtype
malignant
(12 of 20;
immunoglobulin
from
in S weeks,
either
immunologic
features
were
correlated
from
dissemination
using
the actuarial
Meier.’8
polytypic
were
x-rays or cobalt 60 gamma
beams. Patients
with bilateral
disease
had both orbits treated concurrently.
The two patients with inflammatory pseudotumors
who were irradiated
had symptomatic
lesions
refractory
to steroid
therapy.
They were treated
by a similar
technique
to 20 Gy in 2 weeks. Patients
with conjunctival
lymphomas
were treated
with electron
beam irradiation
to 30 Gy in I 2
fractions,
with 6 or 9 mV electrons,
using a specially designed plastic
contact lens bearing lead shielding
for lens protection.
Patients
who
received
expressed
follicular
morphologically
Malignant
lymphoma
cases
ples of reactive
7 mdc-
pseudotumors.
with
Formulation;
common
(50%). Among
the histologically
follicular
lymphomas
were most common
Twenty-one
terminate):
17 received no specific therapy and 4 received radiation.
Two of the four patients
who received radiation
had indeterminate,
polytypic
infiltrates,
in which the pathologist
emphasized
that
lymphoma
could not be excluded,
although
there was no conclusive
immunologic
support for that diagnosis.
The remaining
two patients
irradiated
was the most
60%).
data was unknown.
Of the 20 monotypic
small lymphocytic
infiltrates, I S patients received radiation
alone, 2 chemotherapy
alone, I
both modalities,
I no treatment,
and I was unknown.
Twenty-one
patients
to the Working
lymphoma
age from 25 to 92 with
25 men and 36 women.
2
indeter-
lymphoma
group,
malig(74%)
27
of
The monotypic,
lesions.
according
lymphocytic
Clinicalfeatures.
treatment
20
20 infiltrates
of small
lymphocytes
atypia.
All 40 monotypic
infiltrates
were
subclassified
small
and
included
cytologic
further
cases
indeterminate
group
follicular
therapy
modalities,
minate
atypical)
histologically
indeterminate
lesions
expressed
polytypic
immunoglobulin
only. Two patients had bilateral
biopsies that were histologically
and
immunologically
identical.
Treatment
modalities
were known for 59 patients.
Forty patients
had infiltrates
diagnosed
as lymphoma
by a combination
of morphoalone,
histologically
as malignant
all 20 histologically
ied
(cytologically
I . Thirty-nine
and one case was
(CD
20 antigen
lymphomas.
nant
immunologic
in Table
immunoglobulin
and B lineage
40 infiltrates
This
The
histologicfindings.
results
cases expressed
monotypic
immunoglobulin-negative
in selected
Laboratories,
Immunologic
and histologic
with immunoglobulin
gamma,
RESULTS
da, MD). Monotypic
immunoglobulin
expression
was defined as a
ratio of one light chain to the other of 10 to 1 , as has been proposed
by others.’6 The histologic
and immunologic
features
of these cases
have been reported
in detail elsewhere.’
All patients
initially
presented
with an orbital or conjunctival
lesion. For each case the following clinical data were obtained
from a
review of the hospital
and physicians’
office records:
age, sex,
laterality
(left, right, both), site of the lesion (orbit, conjunctiva),
clinical
stage at diagnosis,
treatment
(irradiation,
chemotherapy,
both, or neither),
and follow-up.
The patients were clinically
staged
and stage was assigned according
to the Ann Arbor staging classification modified for extranodal
lymphoma.”
All patients
were studby
Wilcoxon
test.’9
Formulation.’5
Cryostat
section immunohistochemical
studies
all cases with either a peroxidase-antiperoxidase
1983)
between
histologically
indeterminate)
ET AL
cell;
D-,
diffuse;
SNC.
small
DH. diffuse
pseudotumor.
5CC.
5
small
noncleaved
hyperplasia;
cleaved
cell;
FH, follicular
cell;
SIL,
MC,
small
hyperpla-
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LYMPHOID
Table
LESIONS
2.
Clinical
OF
THE
Features
ORBIT
AND
of Patients
of the Orbit
With
2123
Lymphoid
Infiltrates
nant,
Indet erminate
Malignant
Monotypic
Monotypic
Benign
Polytypic
Polytypic
20
7
Median
70
72
48
55
Range
37-91
35-92
37-78
25-71
dissemination
6 histologically
phoma
.
20
Age
developed
and Conjunctiva
.
No.
CONJUNCTIVA
died
was
with
14
Factors
3),
8 (40%)
9 (45%)
2 (29%)
6 (43%)
monotypic
1 1 (55%)
5 (71%)
8 (57%)
cantly
Bilateral
17(85%)
4 (20%)
7(100%)
14(100%)
0
0
3 (15%)
nant)
18(90%)
Conjunctiva
Lacrimal
6 (30%)
11(79%)
1 (14%)
Not
involved
3 (21%)
3 (15%)
1 (14%)
1 (7%)
17 (85%)
17 (85%)
6 (86%)
13 (93%)
8(40%)
15(75%)
12 (60%)
7(100%)
5 (25%)
(mo)
Range
(mo)
no.
benign
nant
or indeterminate
all cases
5 to 44
of
with
(P
<
risk
indeter-
with
with
histologi-
either
malig-
patients
of dissemination
with
.001).
with
at diag-
for patients
with
parameters
such
no risk
No clinical
(orbit
involvement
conjunctiva;
P = .39)
or
P = .15) correlated
with
v
v bilateral;
(unilateral
histologically
for patients
Similarly,
compared
infiltrates
maligat 5 years
of dissemination
a 70%
had
of dissemination.
.01 compared
<
(Table
(Fig
1A) and
(Fig
2A)
signifi-
(histologically
infiltrates).
34
1-94
2-88
18-79
20-80
6
2
0
0
strongly
ination.
15
11
0
0
50% risk of dissemination
remainder
of the
(6 orbit,
I conjunctiva);
had unilateral
patients
infiltrates
of diagnosis,
At time
phoma
was
proven
the
(32 left,
44 infiltrates
both orbits or conjunctivae,
disease
( I stage III and
For
(Table
localized
4),
correlated
Patients
15 patients,
in
whereas
( I 4 histologically
benign
ized.
17 of
In contrast,
disseminated
at
indeterminate
and
only
site
IV,
stage
semination
cytologically
not statistically
Outcome.
months
differences
indeterminate
significant.
The median
disease
from
patients
with
1 to
44
months
unrelated
the
follow-up
benign
causes
at 26
10 patients
of the remaining
to 94 months).
Nine of 44 patients
9 of I 2
had dis-
between
histologi-
patients
following
was 33
died
months,
to their
was
of
respectively.
deaths,
the
42 months
Total
No.
stage
and
I infiltrates
subsequently
none
Immunologic
for
patients
Parameters
and Dissemination:
All 61 Cases
Disseminated
No.
Dead
No.
P
NS
Men
25
3
36
5
Orbit
49
8
Conjunctiva
12
0
Lacrimal
Pt
10
NS
16
NS
22
NS
4
gland
Involved
9
2
Notinvolved
52
6
Unilateral
54
Bilateral
NS
5
NS
21
(2
8
7
NS
21
0
NS
5
Stage
I
23
lll,IV
17
5
Malignant
20
6
15
M vI
Indeterminate
27
2
11
lvB=
Benign
14
0
0
3
NS
N/A
N/A
class
M vB
<
.05
<
.01
.01
MvB<.001
Ig expression
Monotypic
40
8
Polytypic
21
0
Abbreviations:
cation,
NS,
Ig, immunoglobulin;
not
=03
significant,
M,
Stage
from
for
N/A,
malignant,
dissemination.
monotypic
infiltrates
26
<.01
0
Survival.
tFreedom
with
Histologic,
Survival
Women
Histologic
were
diagnosis.
Two
died secondary
infiltrates
patients
bone
lesions
Eight
and 33
followed
With
with
Side
biop-
without
for all patients
months).
histologically
or
monotypic
follow-up
I to 94
(range,
marrow
lymphomas
with
local-
lymphomas
bone
In contrast,
sites
Clinical.
compared
dissemhad a
Sex
malignant.
lymphocytic
positive
atypical
These
and
malignant
histologically
small
had
(25%)
of dissemination.
involvement.
Excluding
IV
to extramedullary
marrow
20
1 2 of 20 (60%)
stage
were
and conjunctiva
expression
also
Site
lesions were
histologically
monotypic
5 of
monotypic)
sies as their
7 indeterminate)
(43%)
diagnosis;
of 5 (60%)
(indeterminate,
and
40
3.
Patients
in
dissemination
was demonstrated
by radiologic
without
biopsy confirmation.
All polytypic
infiltrates
studies
localized
to the orbit
immunoglobulin
with increased
risk ofsubsequent
with localized
monotypic
infiltrates
Correlated
to one or
and I 7 patients
had disseminated
I 6 stage IV).
Disseminated
lym-
histologically
initially
monotypic
lesions
22 right).
were
patients
median
(P
or subsequently
site
risk
for patients
lesions
lesions
Table
to
For
likelihood
.01) and none
<
33
with
involvement
cally
(P
29
dissemination
(75%)
(range,
atypical
an 80%
45%
with
lesions
laterality
of disease
Three
1 1 months
classification
increased
38
(no.)
two
but
The
dissemination.
Median
Total
had
cally
as
0
Follow-up
Died
lesions
nosis
14(100%)
0
lympatient
performed.
expression
cytologically
polytypic
Disseminated
histologic
with
monotypic
3 (15%)
diagnosis
Localized
malig-
lymphoma,
not
dissemination.
initial
with
minate
gland
Involved
At
6(86%)
14(70%)
2 (10%)
was
was
immunoglobulin
compared
Site
Orbit
of disseminated
autopsy
correlated
Patients
16(80%)
or
influencing
the
both
12 (60%)
Side
Unilateral
evidence
to dissemination
time
(3 histologically
disease
months).
Sex
Men
clinical
biopsy
median
(yr)
Women
proven
antemortem
of
indeterminate).
Disseminated
by biopsy in 8 of 9 patients.
One
only.
not
applicable;
I, indeterminate;
class,
classifi-
B. benign.
From www.bloodjournal.org by guest on July 31, 2017. For personal use only.
2124
MEDEIROS
I©
100
Gehan P-values
1 vs. 2 0.0066
1 vs. 3
0.0001
2 vs. 3
2.
80
_j
60
ET AL
0.0074
40
a.
20
A
2
3
4
5
TIME
1001
.
‘
,-
6
8
7
(YEARS)
.,
-,
P
:
..#{174}
,
.
40
a.
20
1
B
2
3
4
5
TIME
with
polytypic
ically
lesions
(P
and
malignant
<
.005; curve
lesions
equal
frequency
(P = .78),
(P < .05)
and indeterminate
(P
nated
more often than histologically
Histolog-
diagnosis
disseminated
<
both malignant
infiltrates
dissemibenign cases (curves not
.05)
shown).
the 27 patients
For
indeterminate)
tal dissemination
monotypic
immunoglobulin.
whereas
oped
dissemination
logic
parameters
of
lymphocytic
Those
no patients
(P
<
with
.05)
correlated
the
22
to one
or
patients
both
polytypic
(Fig
3A).
with
No clinical
indeterminate
or
conjunctivae
or
5
devel-
also
showed
that
monotypic
immuno-
the cases ultimately
at presentation
lymphomas)
laterality
including
dissemination
as lymphoma
cal lymphomas
cytic
cases,
at time
to be greater
lymphomas
cytologically
or subsequently
(P
P
=
.68).
=
of diagnosis
for patients
compared
with
with patients
.06). However,
atypical
(23
v conjunctiva;
(orbit
v bilateral;
either
appeared
of
site
(unilateral
or histoinfiltrates
diagnosed
tologic
atypia
and/or
monotypic
immunoglobulin
sion), no clinical
parameters
correlated
with increased
Separate
at time
3B)
dissemination
monowith
within
infiltrates
dissemination.
with
orbits
with
of presenting
lymphoma
(Fig
expression
correlated
with subsequent
dissemination; 6 of I 5 patients
with monotypic
infiltrates
subsequently
developed
dissemination
for an actuarial
risk of 50% at 5
years
compared
with
no patients
with polytypic
infiltrates
who developed
dissemination
(P = .06).
Among
(histologically
individuals
had a 62% probability
developing
disseminated
years,
localized
small
infiltrates,
the likelihood
of having extraorbiof disease was correlated
with expression
of
typic infiltrates
subsequently
analysis
with
8
globulin
although
with
7
histoorbital
and conjunctival
infiltrates
correlated
with
dissemination
of
disease
(A)
and
survival
(B). (1 ). Histologically
malignant
(20);
(2).
histologically
indeterminate
(27);
(3). histologically
benign
(14).
(YEARS)
not shown).
indeterminate
6
1.
For all cases.
classification
of
Fig
logic
Gehan P-values
lvs.2
0.1109
1 vs. 3 0.0402
2 vs. 3 0.2925
and small
P
(cyexpresrisk of
localized
=
The overall
.23) and
risk of
or subsequently
cytologically
atypi-
with small
for initially
lympholocalized
lymphocytic
lympho-
From www.bloodjournal.org by guest on July 31, 2017. For personal use only.
LYMPHOID
LESIONS
OF THE
ORBIT
AND
I#{174}Gehan
P-values
CONJUNCTIVA
2125
100
I
vs. 2
0.0000
80
-J
60
4
0
40
a.
0
.
20
1
A
2
3
4
5
TIME
6
7
8
(YEARS)
Inn
80
_J
.
..,
60
4
0
40
a:
a.
Gehan P-values
1 vs. 2 0.0323
20
Fig 2.
For all cases. mono-
typic
immunoglobulin
expression correlated
with dissemination of disease
(A) and survival
(B). (1),
Monotypic
polytypic
(21).
mas
(P
(40);
.48).
Factors
disseminated
Working
dissemination
Formulation
(P
=
with
equal
survival.
classification
immunoglobulin
For
all 6 1 cases
(malignant
v
expression
benign)
occurred
minate
(unilateral
with
bilateral,
v
P
=
.34).
(Table
3),
1B)
and
(Fig
(Fig
with reduced
survival.
No clinical
features
survival
including
site (orbit
v conjunctiva,
laterality
frequency
did not correlate
grade
.5).
influencing
histologic
monotypic
2
2B)
correlated
correlated
with
P = .17) and
Only
in the group of patients
with histologically
infiltrates
precluding
statistical
analysis.
two
deaths
indeterHowever,
both patients
who died had monotypic
lesions.
For the 44 localized
cases (Table
4), three deaths
from
disease occurred.
Although
the number
of events is small, all
three
men
trates
(2 histologically
nate).
who
3
4
TIME
subsequently
=
1
B
(2).
died
had
unilateral,
malignant,
orbital
monotypic
1 histologically
infil-
indetermi-
6
5
7
8
(YEARS)
Among
the cases ultimately
diagnosed
as lymphoma
(cytologic
atypia
and/or
monotypic
immunoglobulin
expression),
Working
Formulation
grade
(low v intermediate
and
high) (P
31 patients
.005) correlated
with low grade
=
of 9 patients
No
clinical
(orbit
intermediate
parameters
and
correlated
v conjunctiva,
bilateral;
influence
patients
P
.1 5) and
=
high
with
laterality
=
Other
than
parameters
Working
correlated
of patients
with cytologically
both low and higher grades)
patients
with
lymphomas
lymphomas),
lymphomas.
including
site
(unilateral
v
did not significantly
survival
for stage I
for stage III and IV
Formulation
with
survival
(includes
lymphocytic
grade
survival
.21). Stage at diagnosis
survival;
the 5-year
actuarial
was 79% compared
with 66%
P
patients.
logic
with
with decreased
survival.
Three of
lymphomas
died compared
with 5
grade,
survival.
The
no pathoactuarial
atypical
lymphomas
was similar
to that of
without
cytologic
88% and 64%,
atypia
(all
respectively,
small
at 5
From www.bloodjournal.org by guest on July 31, 2017. For personal use only.
2126
MEDEIROS
Table
4.
Correlated
Clinical,
Histologic,
With Survival
and Immunologic
and Dissemination:
Total
No.
Dead
No.
P
Men
18
3
=03
Women
26
0
Orbit
34
3
Patients
Parameters
44 Localized
with
Cases
a significant
patients
Eleven
developed
Dissemination
No.
at
Pt
diagnosis
NS
small
Site
Conjunctiva
Lacrimal
10
0
5
0
NS
7
NS
2
Not
involved
39
NS
1
3
41
Bilateral
behavior
of monotypic,
conjunctiva
and
3
3
NS
8
0
NS
8
2
M v B
.09
=
3
Indeterminate
22
1
6
Benign
14
0
0
23
3
2 1
0
See Table
3.
M v B
=
.03
B
=
.03
I
V
MvINS
Monotypic
Polytypic
Abbreviations:
=.09
9
and
of the ocular
follow-up,
incidence
their
study
from
dissemination.
years
(P = .26).
The
patients
with localized
clinical
some
and
low number
lymphomas
pathologic
of deaths
among
the
(three)
precluded
analy-
features
for
this
group
of
patients.
Although
no patients
dissemination
small
lymphocytic
with
infiltrate
later.
lesions
one patient
of the orbit
small
indeterminate,
months
polytypic
of disease,
developed
subsequently
Both
lesions
who
lymphocytic
were
or devel-
populations,
trates.5
morphologically
site
30
indistin-
with
DISCUSSION
included
all
polytypic
infiltrates
that
initially
presented
in the orbit or conjunctiva
in this study, including
patients
in whom staging
workup
revealed
additional
sites of
disease
because
what
constitutes
junctiva.
This
problem
and
findings
within
the
also
of the
orbit
practical
of
patients
in prior
upon
33
require
considered
disease
were
period
of time,
analyzed
the
greatest
because
interest
.06),
Our
(P
monotypic
<
.05)
their
clinical
follow-up
and for
immunoglobulin
iinmuno-
lesions
it appears
and
in
differences
in
that
at least
Jakobiec’2
were
of
extranodal
infil-
the
(9
by
(6 of 20) and their
study
made.
This
Immunologic
case
ratio
in
staging
sequent
if
discovered
of
separately.
with
remains
alive
(median
withfollow
However,
one
local recurrence
of the
recurrent
lesion
need
I
we
was
benign.
initial
the
ratio
in classifying
for caution
as
Although
infiltrate
required
to
malignant
the
did
not
confidently
lymphoma,
sub-
analysis
of both the initial
and recurrent
infiltrates
has revealed
identical
rearrangements
of the immunoglobulin heavy chain gene.22 Thus, it seems probable
that this case
was a lymphoma
from
its inception,
although
below the level
3 months.2#{176}
has shown that
localized
lesions
were
months).
identical
studies
the
rigorous
primary
infiltrates
lesions
to
and conjunc-
lymphocytic
monotypic
immunoglobulin
expresof small lymphocytic
lymphoma
was
illustrates
lambda
of small
at last follow-up
indeterminate
to
nature
conjunctiva
that do not express
All of the patients
in this study
I 8 to 79
infiltrate
correlated
of
disseminated
of dissemination
a histologically
demonstrated
obvious
sion and the diagnosis
kappa
this
range,
an
expression
of
those
initial
reflect
study
lymphocytic
10
significance
analysis
the 22
may
the
study
that
lesions
predictor
from
lesions compared
disseminated.
The
Knowles
in our
the
for example,
localized
in
approach
subsequently
by
small
mono-
by the polytypic
incidence
determine
be
monotypic
infiltrates
the
biopsy
to
of the
lymphoma
months;
developed
polytypic
con-
to
ultimately
to our study,
initial
the
studies#{176}2’orbital
not
and
solution
using
criteria
group of 27 cases classified
as histologically
indeter(small
lymphocytic
infiltrates)
in this report
is of
controversial.”457”2
for all cases
=
of
agreed
disease
is our
were
an arbitrary
have
presently
benefit
which
However,
sites
we
The
minate
(P
approach
has
lymphomas
additional
no
primary
to predict
evaluation.
Thus,
are
there
adnexa
of the true
small
at 30 months.
lymphoid
of
30% of 54 lympho-
regardless
of the orbit and
immunoglobulin.
out disseminated
up,
have
infiltrates
infiltrates
monotypic
patient
We
that
our own
particularly
Interestingly,
is identical.
We are less certain
(histo-
same
group
and
conjunctiva,
to differ
found
reported
too
clinical
of 30)
was not treated
the
cases
the
studied
by cell suspension
and flow cytometry
techniques.
Frozen section immunohistochemistry
may be more sensitive
than cell suspension
methods
in detecting
small monoclonal
a polytypic,
lymphoma
at
monotypic)
died
with
guishable.
tival
In contrast
monotypic
oped
with
both
are
of dissemination
and
of dissemination
compared
of the
numbers
is a significant
status;
9 of 30 (30%)
of 24 (29%)
polytypic
7
of disease;
Thus,
appear
who
a 3-year
methodology.
tFreedom
logically
Jakobiec’2
infiltrates
higher
#{149}Survival
results
with
with
.002
0
died
the
orbit
expression
Our
disseminated
(median,
11
these
within
the
cytic
globulin
Ig expression
of
behavior.
evaluation
lymphocytic
infiltrates
of the
to that of other
low grade B
that,
of
immunoglobulin
Knowles
Malignant
indicate
infiltrates
staging
significance.
small
infiltrates
clinical
but
a significant
risk
clinical
course.
with
indolent
results
typic
1
patients
is similar
lymphomas,
Our
two
infiltrates,
statistical
orbit
8
class
Histologic
for
achieve
lymphocytic
Unilateral
only
monotypic
a relatively
NS
Side
sis
to
cell
gland
Involved
had
lymphoma.
stage I cases
after diagnosis
5 to 41 months
However,
patients
6
5 had a positive
6 of 20 (30%)
and
months).
3
disseminated
indeterminate
monotypic,
dissemination;
subsequently,
Sex
risk ofdeveloping
with
ET AL
by
immunohistologic
polytypic
orbital
detection
five
reported
by Neri
had heavy chain
that
these
ever,
all
et al’4; in that study
gene rearrangements,
infiltrates
three
studies.
lesions
were
infiltrates
also
been
results
previously
three polytypic
cases
perhaps
suggesting
malignant
had a benign
Similar
have
lymphomas.
How-
clinical
course
in that
the
nature
of the
study.
Despite
the
uncertainty
regarding
true
From www.bloodjournal.org by guest on July 31, 2017. For personal use only.
LYMPHOID
LESIONS
OF
THE
ORBIT
AND
2127
CONJUNCTIVA
100
80
-J
60
4
0
a:
a.
.
40
#{149}0
Gehan
20
P-values
1 vs. 2
1
A
2
3
4
TIME
0.0183
5
6
7
5
6
7
(YEARS)
100
80
-J
Fig 3.
For
all 27
4
(A)
‘a
and for the 22 localized
lesions
(B). monotypic
immunoglobulin
0
cally
indeterminate
expression
cases
correlated
with
these
cases
in-
20
2
1
B
lesions,
disseminate
at
our results
a lower
suggest
frequency
that
or
than lesions that are monotypic
by immunohistologic
na. Monotypic
infiltrates,
by definition,
have a tumor
of this clone. Polytypic
lesions with
ments
may
have a much
smaller
although
these lesions may eventually
the probability
less and/or
These
small
take
results
of this
criteclone
a longer
may
lymphocytes
clonal gene rearrangeneoplastic
clone,
and
be found to dissemi-
occurrence
time
may
occur
be significantly
to dense
at other
infiltrates
extranodal
sites,
of
such
as the gastrointestinal
tract,24
lung,25’’
and skin.8 In these
sites lesions that would have been diagnosed
as pseudolymphoma
using
express
monotypic
histologic
criteria
immunoglobulin.
alone
The
have
clinical
been
found
significance
(YEARS)
infiltrates
orbit
and
has been
conjunctiva
questioned.23’24’26
suggest
extranodal
sites are indolent,
with potential
for dissemination.
low
that
grade
B-cell
of orbital
and conjunctival
to the Working
Formulatio&5
appears
in predicting
Patients
with
better
survival
survival,
although
not
low grade
lymphomas
than
that
of those
and
Jakobiec
who
showed
similar
results
cases
Subclassification
according
(includes
revealed
no significant
dissemination,
supporting
in
in other
lymphomas
lymphomas
to be useful
risk of dissemination.
had a significantly
with
intermediate
results
or high
stage
those
I
lesions,
of Knowles
using
the
port classification.’
Comparison
of small lymphocytic
phomas (indeterminate,
monotypic)
with cytologically
cal lymphomas
to
Our
such
grade
lymphomas
(all
cases,
P < .005;
P = .09). These results are in accord with
to occur.
also be applicable
that
of these
the
later
that is large enough
to be recognized
by immunohistologic
methods.
The risk of dissemination
may be related to the size
nate,
4
3
TIME
and polytypic
may
40
a:
a.
creased
likelihood
of dissemination
of disease.
(A):
(1).
Indeterminate
and monotypic
(20);
(2).
indeterminate
and
polytypic
(7).
(B): (1). Localized. indeterminate
and monotypic
(1 5); (2). localized.
indeterminate
and polytypic
(7).
indeterminate
60
‘a
histologi-
low and higher
grade
Rappalymatypi-
lymphomas)
difference
in survival
and risk of
the concept
that small
lympho-
From www.bloodjournal.org by guest on July 31, 2017. For personal use only.
2128
MEDEIROS
cytic
infiltrates
that
express
malignancies.
If immunologic
monotypic
immunoglobulin
are
true
data
criteria
histologic
mation
regarding
to
greatest
with
evidence
of
follow-up.
In prior
lymphoid
have
analyses,
there
a better
was
not
infiltrates.
In
this
(6 of 20;
were
lymphoma
at
that
last
than
in this
orbital
study.
our
data
the results of Ellis et al28 who also found
features
or difference
in behavior
between
are
staged
for
similar
are biopsied.
lesions
A second
to
in this
.
2.
DM,
Clinical,
Jakobiec
FA:
histopathologic,
characteristics.
3. Jakobiec
FA,
Ocular
adnexal
electron
Hum
McLean
of orbital
teristics
survival
the
Turner
RR,
conjunctiva
cases.
lymphoid
neoplasms.
patients
less clear
nation
Am
Egbert
and
J Clin
A 5-year
J Ophthalmol
8.
treatment
the
because
with
these
be
incidence
polytypic
rigorously
lesions in this
studies may be
infiltrates.
The
lymphocytic
patients
small
of dissemination
all polytypic
that staging
small
of
and
conjunctiva
that patients
with
should
a high
with
therapy,
role for
lymphomas
have an incidence
the relatively
of lymphoma
appeared
suggests
that local
the indolent
nature
of
is
of dissem-
disseminated
high
frequency
in the patients
in this
to be localized
at the time
therapy
of these
disease,
of dissemi-
series,
even
when
of diagnosis,
may not be curative.
However,
lymphomas,
even in the presence
argues
against
aggressive
initial
treatment.
ACKNOWLEDGMENT
The
authors
thank
access
the following
to their
office
physicians
records:
who graciously
Richard
Dallow,
pro-
MD,
Arthur
Samuel
Jr. MD, Gary Borodic,
MD, Francis
Sutula,
MD, John
MD, and Zareh Demerjian,
MD. The authors
also thank
A. Brian, PhD, for his advice during the statistical
analysis
of
work
this
13:148,
I, Font
RL:
neo-
and
immu-
and
with
Althea
the
P. Warnke
orbit.
Pathol
RA:
Williams
immunologic
Lymphocytic
and
Bruce
Kaynor
for
their
tumours
in the
orbit.
analysis
of extrano-
studies.
staining
Evans
clinicopathologic
follow-up
Pathol
2:163,
13.
Jakobiec
of
I6
62:381,
HL:
orbital
lesions.
Br
1978
Extranodal
and
and
small
immunocytochemical
lymphocytic
proliferations:
study.
Cancer
A
49:84,
lymphoreticular
To
or polyclonality
lymphoma
1984
of 98 conjunctival
infiltrates:
86:948,
of
Primary
1975
DM, Jakobiec
lymphoid
charac-
infiltrates
CIV:
26:137,
Knowles
I 2.
mono-
Ophthalmology
Immunohistochemical
81:447,
Franklin
.
Radiol
dal
1982
Clinicopathologic
hyperplasia.
I I
Clin
lymphoid
microscopic,
Pathol
A
1980
5. Harris
NL, Harmon
DC, Pilch B, Goodman
ML, Bhan A:
Immunohistologic
diagnosis
of orbital
lymphoid
infiltrates.
Am J
Surg Pathol 8:83, 1984
6. Medeiros
Li, Harris NL: Lymphoid
infiltrates
of the orbit and
conjunctiva.
A morphologic
and immunophenotypic
study of 99
cases. Am i Surg Pathol 1 3:459, 1989
7. Morgan
G, Harry i: Lymphocytic
tumours
of indeterminate
nature:
and
In contrast,
suggesting
in patients
for
assistance
1979
4.
have
staging
Grove,
Woog,
small
for
bilateral
decreased
DM, Jakobiec
FA: Orbital
lymphoid
study of 60 patients.
Cancer 46:576,
Knowles
nologic
did not portend
they
of low yield
vided
the number
was too
Similarly,
for
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1 Knowles
clinicopathologic
plasms:
to be achieved.
study
lymphoid
suspicious
is that
( I 2) in our study
of conjunctival
lesions
statistical
significance
involvement
possibility
staging
lymphomas
atypical
the lesions
no distinguishing
orbital
and con-
selecting
patients
with
conjunctival
have changed,
so that only clinically
for
at time of diagnosis.
study were localized,
junctival
lesions.
The reason
for the discrepancy
between
more
recent2’
and earlier
results217
is unclear;
possibly
the
criteria
infiltrates
routine
because
Regarding
By all
in survival
or freedom
from
with conjunctival
or orbital
respect,
support
unilateral
lesions as
only seven bilateral
ination
at time of diagnosis
intermediate
between
that of
cytologically
atypical
lymphomas
and polytypic
infiltrates.
conjunctival
prognosis
confirmed
optimal
cytologically
at
the
infiltrates
suggested
was no difference
between
patients
dissemination
lymphoid
This
The
of dissemi-
to disease
providing
both bilateral
and
our study included
lymphocytic
lymphomas
of the orbit
remains
controversial.
Our data suggest
and
cytologically
dissemination
benign
of dissemination
lesions.
as malignant
Histologically
and
risk
practice
of staging
stage lE. However,
alone,
I 2; 75%),
disseminated
infiltrates
infor-
criteria
incidence
of
secondary
it has been
lesions.
(9
histologically
studies2127
lymphoid
of
the highest
of deaths
All patients
without
histologic
sites
by
if incomplete
(monomorphous
highest
incidence
extramedullary
number
30%).
classification
useful
reliably
classified
(all
polytypic).
(12 of 20; 60%),
nation
available,
Using
cases were
or benign
infiltrates
had the
diagnosis
not
provides
prognosis.
34 of 61 (56%)
(all monotypic)
malignant
atypical)
are
alone
or increased
ET AL
FA: Cell marker
what
extent
does
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v pseudolymphoma
in an
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of
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Diagn
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1989 74: 2121-2129
Immunohistologic features predict clinical behavior of orbital and
conjunctival lymphoid infiltrates
LJ Medeiros, DC Harmon, RM Linggood and NL Harris
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