Unilateral Proptosis and Diplopia Lara Rosenwasser Newman, MD University of Louisville Department of Ophthalmology and Visual Sciences September 4, 2015.

Unilateral Proptosis and Diplopia

Lara Rosenwasser Newman, MDUniversity of Louisville

Department of Ophthalmology and Visual Sciences

September 4, 2015

SubjectiveCC: 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.

HistoryPMHx: 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

IOP: 13mmHg24mmHg

EOMs:

CVFs: full fullHertels: base 93 14 mm

23 mm

Clinical Exam OD OSVA: 20/30 20/50

CC: -1.00 +0.75 x147 M: -1.50 +0.75 x075

Pupils: 5 5; +rAPD

0

0

0

0 0

-1

0

-2

Clinical ExamPLE: OD OSExternal/Lids WNLproptosis Conjunctiva/Sclera clear/white mod injection,

mod to severe chemosisCornea arcus senilisarcus senilisAnterior Chamber deep & quietdeep & quietIris WNL WNLLens 1+ NS 1+ NSVitreous WNL 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

Pathology – H&E

Diffuse proliferation of large pleomorophic neoplastic lymphoid cells w/focal necrosis, w/invasion into vessel walls, brisk mitotic activity, monomorphic and polymorphic patterns

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

CD20

Membrane stains dark brown if CD20 positive

Positive for:

BCL-2 & BCL-6(focal) Translocations of both genes seen in many

lymphomas

MUM-1 = multiple myeloma-1: 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 CD3-positive 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

Cyclin D1 aka BCL-1 (B-cell lymphoma-1)

Follow-up

4 cycles chemo w/DA EPOCH-R regimen Dose-adjusted Etoposide, Prednisolone,

Oncovin (Vincristine), Cyclophosphamide, Hydroxy-daunorubicin (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 Low grade lesion of small, mature-

appearing lymphocytes #3: Follicular center lymphoma

Low grade lesion w/follicular centers #4: High-grade lymphomas

including: Large cell lymphoma Lymphoblastic lymphoma Burkitt lymphoma

Study done in Denmark to characterize features of DLBCL of ocular adnexal region, 1980-2009

34 pts, median age 78 (range 35-97) 97% unilateral ocular adnexal involvement, 76% in the

orbit 56% (19) presented w/Stage I lymphoma – 18 had

primary lymphoma Primary defined as ocular adnexal lymphoma with no other

systemic involvement 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) scoreonlinelibrary.wiley.com/doi/10.1111/j.1755.../pdf

Treatment Options

References1. Pathologyoutlines.com2. 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.

3. http://training.seer.cancer.gov/lymphoma/abstract-code-stage/staging.html4. 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 A = circumferential halo, B = elevation – nasal border, C = no major

vessel obscuration 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 = 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

lymphomasNote: 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)