Unilateral Proptosis
and Diplopia
Lara Rosenwasser Newman, MD
University of Louisville
Department of Ophthalmology and Visual Sciences
September 4, 2015
Subjective
CC: red swollen left eye x 3 weeks
HPI: 73 year old Caucasian female with history of
progressive swelling of LUL and redness of OS
x 3 weeks, accompanied by diplopia. Felt her
vision was worse, had pain around the eye, and
was experiencing watering and foreign body
sensation OS.
History
PMHx: Rheumatoid arthritis, GERD, coronary artery disease
PSHx: Hysterectomy, coronary stent 2006, cholecystectomy,
appendectomy
POHx: None
Medications: Losartan, Metoprolol, Methotrexate, alendronate,
atorvastatin, 81 mg aspirin, folic acid, Vit D, multivitamin,
fish oil, Tums
Allergies: sulfa, PCN, MRI contrast, levofloxacin
Clinical Exam
VA:
OD
20/30
OS
20/50
CC: -1.00 +0.75 x147
M: -1.50 +0.75 x075
Pupils:
IOP:
EOMs:
5
5; +rAPD
13mmHg
24mmHg
0
-1
0
CVFs:
Hertels: base 93
0
0
full
14 mm
0
-2
0
full
23 mm
Clinical Exam
PLE:
External/Lids
Conjunctiva/Sclera
OD
WNL
clear/white
Cornea
Anterior Chamber
Iris
Lens
Vitreous
arcus senilis
deep & quiet
WNL
1+ NS
WNL
OS
proptosis
mod injection,
mod to severe chemosis
arcus senilis
deep & quiet
WNL
1+ NS
WNL
DFE: OD WNL, OS: 2-3+ disc edema, choroidal folds present
MRI

Done at outside hospital
 “Abnormal, slightly heterogeneous but primarily intermediate
signal or soft tissue signal focus at the lateral, superior, and mid
to anterior aspect of the left orbit. This finding appears to be
separate from the rectus musculature and optic nerve of left orbit
but it produces mass effect on these structures.”
 “Mass effect on the left globe which is slightly displaced anteriorly
and medially…. Partial proptosis of the globe… slight extension
along the left lateral and anterior superior margin of the left globe.”
 Mass: 3.5 x 2.2 x 2.1 cm (AP by transverse by craniocaudal)
 “Most consistent with a soft tissue mass – DDx incl hemangioma,
orbital melanoma, metastasis”
 Evidence of chronic sinusitis
Assessment

73 year old Caucasian female with proptosis,
APD, disc edema, and choroidal folds OS, and
diplopia with a superolateral orbital mass
Plan

Take to operating room for lateral orbitotomy
with bone flap for mass biopsy

Some infiltration of extraocular muscles upon
exploration

Fresh pathology sent during procedure
consistent with lymphoid type
Follow-up

Post-operative week #1:
20/30 OD, 20/50 OS cc, ph OS 20/40
 No APD
 + LUL ptosis & edema



Pathology: lymphoma, not yet classified
Discussed oncology referral with primary care
Patient Name
Pathology
–
H&E
Crawford, Nancy J

Diffuse proliferation of
large pleomorophic
neoplastic lymphoid
cells w/focal necrosis,
w/invasion into vessel
walls, brisk mitotic
activity, monomorphic
and polymorphic
patterns
H&E
Positive for:

CD19 weakly: seen on follicular dendritic cells and all
B-cells (lost by maturation to plasma cells)

CD20 strongly: seen on late pro-B cells through
memory cells (not on early pro-B or plasma blasts or
plasma cells)

Also on B-cell lymphomas, hairy cell leukemia, B-cell CLL, &
melanoma cancer stem cells
Order #
CD20 15-33734
CD20
Membrane stains dark brown if CD20 positive
Positive for:

BCL-2 & BCL-6(focal)


MUM-1 = multiple myeloma-1:



Translocations of both genes seen in many lymphomas
protooncogene of hematologic neoplasia
B-cell marker found in normal lymphoid tissues & lymphoma
CD43 (focal): Pan T cell marker important in T cell and
neutrophil adhesion to endothelium
Dx at 3 week time point

High-grade B-cell lymphoma
Strong CD20 membrane immunostaining
 Ki67 score of 70% (high)



Based on amt of Ki67 antigen, a marker of cellular
proliferation
Immunohistochem stain for EBV neg, FISH for
EBER was negative twice but could be false neg
DDX

EBV-positive diffuse large B-cell lymphoma of
the elderly (EBV+ DLBCL)

B-cell lymphoma, unclassifiable, with overlap
features between DLBCL and Burkitt
lymphoma (“double-hit” lymphoma)

DLBCL with activated B-cell phenotype
Pathology report addendum


Diffuse large B-cell lymphoma
Focus of cyclin D1-positive small B-cells

“Vaguely nodular proliferation of large atypical
lymphoid cells… admixed sclerosis… numerous
mitotic figures… scattered large tumor cells”

No Reed-Sternberg cells seen (Hodgkin’s)
Pathology report addendum

Diffuse area of large tumors cells positive for:
CD20, PAX-5, CD30, BCL-2, BCL-6, MUM-1
 Neg for CD5, CD23, cyclin D1, CD43


High proliferative rate

Focus of small lymphoid cells containing
mixture of CD20-positive B-cells and CD3positive T-cells
Pathology report addendum

FISH neg for BCL-2 rearrangement and c-myc

FISH for cyclinD1/IgH rearrangement sent to
evaluate for possible concurrent mantle cell
lymphoma

Negative for CCND1/IgH rearrangement
Specimen
#
Cyclin
Case #
D1 aka BCL-1
52587058-SF
52613476
(B-cell lymphoma-1)
Cyclin D1
H&E
CD20
Cyclin D1
Marker
Result
Description
CD30
CD20
PAX-5
Positive
Positive
Positive
CD3
T-cells Positive
CYCLIN D1
CD5(4C7)
CD10
CD23
CD43
CYCLIN D1
BCL-2 IHC
BCL-6
CD21
IgD (p)
KAPPA IHC
Ki67
LAMBDA IHC
MUM1
CD68
Some B-Cells Positive
T-cells Positive
Equivocal
Negative
T-cells Positive
Some Cells Positive
Positive
Positive
Negative
Few B-Cells Positive
Plasma Cells Positive
70%
Plasma Cells Positive
Positive
Histiocytes/macrophages Positive
Activated T, B, Reed-Sternberg Cells, ALCL (Ki-1, BerH2)
Pan B Cell Antigen (L26)
B cell and Hodgkin's Lymphoma
Pan T Cell, Epsilon Sub-Unit of the CD3 T Cell Receptor
Complex
Mantle Cell Lymphoma (Cyclin D1, PRAD-1)
Pan T Cell Antigen, Mature B Cell Subset, Thymic Carcinoma
Follicle Center B Cells, CALLA (B and T ALL)
Low Affinity IgE Receptor, Mature B Cells, CLL/SLL
T Cells, B Cell Subset, Myeloid Cells, Histiocytes (Leu22)
Mantle Cell Lymphoma (Cyclin D1, PRAD-1)
Anti-Apoptosis Protein, Follicular Lymphoma, B Cell Subset
Follicle Center B Cells
C3d and EBV Receptor, Mature B Cells, Follic. Dendritic Cells
Immunoglobulin D Heavy Chain
Kappa Immunoglobulin Light Chain, B Cells and Plasma Cells
Cell Proliferation Marker (MIB-1)
Lambda Immunoglobulin Light Chain, B Cells and Plasma Cells
Plasma Cells Post Germinal Center B-Cells, Activated T-Cells
Macrophages and Myeloid Cells (KP1)
Marker
Result
Description
EBER ISH
Negative
Epstein- Barr Virus Early RNA (by ISH)
Known positive cells or tissues are tested with each marker, examined to ensure positivity, and returned with each case.
Electronically Signed By
Date
Follow-up

4 cycles chemo w/DA EPOCH-R regimen

Dose-adjusted Etoposide, Prednisolone, Oncovin
(Vincristine), Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Rituximab

Found to have parotid involvement

Good response to chemo on PET scan
Follow-up

Developed peritonitis after 4th treatment
Had sigmoidectomy for sigmoid perforation
 Persistent hazy opacities in left lung base on imaging


Resp status rapidly deteriorated as inpatient

Passed approx. 4 months after tumor removal
Lymphoproliferative disorders
of the orbit


>20% of orbital tumors
Most are B-cell lymphomas
Malignant non-Hodgkin lymphomas (NHL) -> 90%
of orbital lymphoproliferative disease
 T-cell types rarer and more lethal


Increased risk of NHL with: long-term exposure
to bioactive solvents and reagents, older age, and
chronic autoimmune disease
Lymphoproliferative disorders
of the orbit

#1 MALT (mucosa-associated lymphoid tissue)
lymphoma: 40-60% of orbital lymphomas
? association w/chlamydial infections
 In orbit, not associated w/mucosal tissue ie
conjunctiva or lacrimal gland
 Low grade of malignancy
 15-20% transform to high-grade, usually large-cell

Lymphoproliferative disorders
of the orbit

#2: CLL = Chronic lymphocytic lymphoma


#3: Follicular center lymphoma


Low grade lesion of small, mature-appearing
lymphocytes
Low grade lesion w/follicular centers
#4: High-grade lymphomas including:
Large cell lymphoma
 Lymphoblastic lymphoma
 Burkitt lymphoma

Diffuse large B-cell lymphoma
of the ocular adnexal region:
a Opht hal mol ogica 2013
A Act
nation-based
study
Diffuse large B-cell lymphoma Peter K . Rasmussen, Elisabeth Ralfkiaer, Jan U. Prause,
L ene D. Sjo¨, Peter B. Toft, Volkert D. Siersma and
of the ocular adnexal region:
Steffen Heegaard
A nation-based
study
Diffuse
large B-cell
lymphoma
of Peter
the
ocular
adnexal
region:
K . Rasmussen,
Elisabeth
Ralfkiaer,
Jan U. Prause,

Study
done
in
Denmark
to characterize features of DLBCL of
L ene D. Sjo¨, Peter B. Toft, Volkert D. Siersma and
A Steffen
nation-based
study
Heegaard
ocular adnexal region, 1980-2009
Peter K . Rasmussen, Elisabeth Ralfkiaer, Jan U. Prause,
34
pts,
median
age
78and(range 35-97)
L ene
D. Sjo
B. Toft,
Volkert D.
Siersma
¨, Peter
1
2
2
3
1
4
1,3
1
1
2
2
3
1
4
1,3
Department of Neuroscience and Pharmacology, Eye Pathology I nstitute,
University of Copenhagen, Denmark
2
Department of Pathology, Copenhagen University Hospital, Denmark
3
Department of Ophthalmology, University of Copenhagen, Glostrup Hospital,
Denmark
4
I nstitute of Public Health, The Research Unit and Section of General Practice,
University of Copenhagen, Denmark
1
Department of Neuroscience
and Pharmacology,2 Eye Pathology I nstitute,
1
1
University of Copenhagen, Denmark
2
3
4
2
Department of Pathology, Copenhagen University Hospital, Denmark
3
1,3
Department
of Ophthalmology,
University of Copenhagen, Glostrup Hospital,
Steffen
Heegaard
Denmark
Public Health, The Research Unit and Section of General Practice,
4
1
I nstituteofofNeuroscience
Department
and Pharmacology, Eye Pathology I nstitute,
University
of Copenhagen,
Denmark
University
of Copenhagen,
Denmark
97% unilateral ocular adnexal involvement,
ABSTRACT. 76% in the orbit
Purpose: To characterize the clinicopathological features of diffuse
B-cell lymphoma
(DL BCL
) of primary
the ocular adnexal
region.
56%Copenhagen
(19) presented
I lymphoma
– 18
had
lymphoma
Department of
Pathology,
University Hospital,w/Stage
Denmark
large
2
M ethods: The present series of orbital and adnexal DL BCL s were found by
searching the
Danish
Pathology between
1980 and 2009. HistologPrimary defined as ocular adnexal lymphoma
with
noRegistry
otherofsystemic
involvement
ical specimens were re-evaluated using a panel of monoclonal antibodies. Clinical files from all patients with confirmed DL BCL were collected.

ABSTRACT.
Results: A total of 34 patients with DL BCL of the ocular adnexal region were
Purpose: To characterize the clinicopathological features of diffuse large Introduction
identified. Eighteen of the patients were men. The patients had a median age
B-cell lymphoma (DL BCL ) of the ocular adnexal region.
Diffuse large B-cell
lymphoma
of 78 years (range 35–97 years). Ninety-seven per cent of the patients had uniM ethods: The present series of orbital and adnexal DL BCL s were found by (DL BCL ) has an aggressive clinical
lateral ocular adnexal region involvement, and the orbit (76%) was the most
searching the Danish Registry of Pathology between 1980 and 2009. Histolog- course and is the most common lymfrequently
Nineteen 25–30%
patients (56%) presented with Stage I lymphoma affected
subtype,site.
representing
ABSTRACT.
ical specimens
 were re-evaluated using a panel of monoclonal antibodies. Clini-Introduction
phoma.
Of
these,
18
were
diagnosed
with primary lymphoma. Four patients
of all lymphomas in Western counPurpose:
To from
characterize
thewith
clinicopathological
features
of diffuse large
cal files
all patients
confirmed DL BCL
were collected.
(12%)
had
Stage
I
I
,
one
patient
(3%)
had Stage I I I and ten patients (29%)
tries (The
L ymphoma
B-cellResults:
lymphoma
(DLof
BCL
of the ocular
adnexal
region.
Diffuse
largeNon-Hodgkin’s
B-cell
lymphoma
A total
34)patients
with DL
BCL of
the ocular adnexal region were
presented
with
Stage
I
V
lymphoma.
The
5-year overall survival (OS) rate for
Classification
Project
1997).
It
is
(DLBCL) has an aggressive clinical
M ethods:
The present
of patients
orbital and
DLpatients
BCL s were
by age
identified.
Eighteenseries
of the
wereadnexal
men. The
had found
a median
the
whole
study
group
was
20%.
The
patients
with Stage I lymphoma had a
defined
as
a
neoplasm
consisting
of
a
course and is the most common lymsearching
Danish
Registry
of Pathology
betweenper
1980
2009.
Histologof 78 the
years
(range
35–97 years).
Ninety-seven
centand
of the
patients
had unisignificantly
better
5-year
OS
rate
(28%)
than
patients
in Stage I I -I V (5-year
diffuse
growth
pattern
of
large
B
phoma subtype, representing 25–30%
ical specimens
wereadnexal
re-evaluated
using
a panel ofand
monoclonal
lateral ocular
region
involvement,
the orbit antibodies.
(76% ) wasClinithe most
OS
rate,
9%).
I
n
Cox
regression
analysis,
concordant
bone marrow involvecells
with
a
nuclear
size
twice
that
of
of
all
lymphomas
in
Western
councal files
from allaffected
patientssite.
withNineteen
confirmed
DL BCL(56%
were
collected. with Stage I lymfrequently
patients
) presented
normal
lymphocytes
or Prognostic
equal to or
ment
and
the
I
nternational
I
ndex
(I
PI
)
score
were prognostic factries
(The
Non-Hodgkin’s
Lymphoma
Results:
A total
34 patients
DL BCLwith
of the
ocular lymphoma.
adnexal region
phoma.
Of of
these,
18 werewith
diagnosed
primary
Fourwere
patients larger than the size of normal macrotors
for
OS.
Classification
Project
1997).
It
is
identified.
of the
patients
were
men.
The
patients
had ten
a median
(12% )Eighteen
had Stage
I I , one
patient
(3%
) had
Stage
I I I and
patientsage
(29% ) phage nuclei (Swerdlow et al. 2008).
onlinelibrary.wiley.com/doi/10.1111/j.1755.../pdf
defined
as a neoplasm
consisting
a
Conclusions:
Diffuse large
B-cellof lymphoma
of the ocular adnexal region is
of 78presented
years (range
35–97
years).
Ninety-seven
per
cent
of
the
patients
had uniwith Stage I V lymphoma. The 5-year overall survival (OS)
rate for
Patients
arepattern
usually
the
seventh
diffuse
growth
ofin large
B M ost patients had unilateral orbital
mainly
prevalent
in elderly
patients.
3
Department of Ophthalmology, University of Copenhagen, Glostrup Hospital,
Denmark

4
I nstitute of Public Health, The Research Unit and Section of General Practice,
University of Copenhagen, Denmark
12% Stage II, 3% (1 pt) Stage III, 29% Stage IV

5 yr overall survival rate was 20%
Worse prognosis with bone marrow involvement and high IPI
(International Prognostic Index) score
I
D
(D
co
p
o
tr
C
d
d
ce
n
la
p
P
d
ti
fo
(S
w
re
Treatment Options
References
1.
2.
3.
4.
Pathologyoutlines.com
Rasmussen PK, Ralfkiaer E, Prause JU, Sjö LD, Toft PB, Siersma VD, Heegaard S. Diffuse large
B-cell lymphoma of the ocular adnexal region: a nation-based study. Acta Ophthalmol. 2013
Mar;91(2):163-9. doi: 10.1111/j.1755-3768.2011.02337.x. Epub 2012 May 2. PubMed PMID:
22551232.
http://training.seer.cancer.gov/lymphoma/abstract-code-stage/staging.html
BCSC Orbit,Eyelids, and Lacrimal System 2014-2015 (Section 7) pp 79-83
Modified Frisen Scale
for Disc Edema


Stage 0: Normal
Stage I: Minimal

A: C-shaped halo that is subtle and grayish with a temporal gap; obscures underlying retinal details

B: Disruption of normal radial NFL arrangement striations
C: Temporal disc margin normal


Stage II: Low degree


Stage III: Moderate


A = obscuration of vessels leaving disc, B= circumferential halo, C = elevation of all
borders, D = halo – irregular outer fringe w/finger-like extensions
Stage IV: Marked


A = circumferential halo, B = elevation – nasal border, C = no major vessel obscuration
A = total obscuration of a vessel leaving disc, B = elevation of entire nerve head including
cup, C = complete border obscuration, D = complete halo
Stage V: Severe - Partial obscuration of all vessels on disc and total obscuration of at
least one vessel on disc
Follow-up

Negative for BCL-2 rearrangement on FISH


Translocation present in 70-90% of follicular
lymphomas, 10-30% of diffuse large cell lymphomas
Negative for BCL-6 rearrangement

B-cell NHL carry greatest number of BCL-6
translocations


15-40% of diffuse large B-cell lymphoma, 6-15% of
follicular lymphomas, & 50% of nodular lymphocyte
predominant Hodgkin lymphoma
More favorable prognosis if increased expression
Did NOT express:


CD3 aka OKT3: T-cell marker
CD5: Marker for CLL, mantle cell lymphoma (rarely), T cells
(normal and malignant), thymic carcinoma, some low grade B
cell lymphomas

CD10 aka CALLA (Common Acute Lymphoblastic
Leukemia Antigen): normal & neoplastic hematopoietic cells

CD23: dendritic cell & B-cell marker
BCL-1: oncogene, encodes cyclin D1


Seen in B-cell leukemias and lymphomas
Note: many of these are seen in many other malignancies;
focusing just on hematologic malignancies here
Ann Arbor Staging of Lymphoma
Stage I also: single extranodal organ (Ie)
Stage II also: single extranodal organ
plus its regional lymph nodes with or
without other nodes on same side of
diaphragm (IIe)
Ann Arbor Staging of Lymphoma
Stage III also: localized involvement of
extralymphatic organ or site plus nodes
on both sides of diaphragm (IIIe) OR
involved lymph nodes on both sides of
diaphragm plus spleen (IIIs)