OCULAR LYMPHOMA

Lymphoid tumors represent ~10% of biopsy-

proven orbital disorders

Lymphatic tissues do not exist in orbit.

Point of dispute

Orbit contains scattered lymphocytes.

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Ocular lymphoma

Orbit is an extranodal site

Depending on the site of involvement,

Orbital

Adnexal

Intraocular

Distribution of common lymphoproliferative lesions of the orbit.

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Ocular manifestationsFrequently masquerade as other more benign intraocular

conditions

Proptosis

Visible conjunctival mass

Allergic or infectious conjunctivitis

Uveitis

Multiple evanescent white dot syndrome

Acute retinal necrosis

Herpetic retinitis.

Orbital & Adnexal lymphoma

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Orbital and ocular adnexal lymphoma

Insidious onset

Progress over a year before producing symptoms.

Symptoms :20 to pressure effects on surrounding structures.

Clinical features

Painless proptosis with or without motility disturbances

Double vision

Ptosis

Decreased vision.

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Orbital and ocular adnexal lymphoma

Unilateral or bilateral.

More common in the anterior superior orbit.

Preseptal portion of the eyelid can be involved.

Usually rubbery to firm on palpation

No palpable bony destruction.

The lacrimal gland, lacrimal sac, EOM can be

similarly involved.

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Systemic disease to be suspected

Cervical lymphadenopathy,

Preauricular lymphadenopathy

Parotid gland swelling

Abdominal mass

Thorough physical evaluation

Of primary orbital lymphoid lesions,

50% reactive or atypical hyperplasia

50% malignant lymphoma.

Recent evidence, show systemic disease occurring in

15% to 25% of reactive hyperplasias,

40% of atypical hyperplasias,

20% of well-differentiated lymphomas, and

60% of poorly differentiated lymphomas.

Reactive lymphoid hyperplasia of the bulbar conjunctiva and upper fornix.Appearance is similar to that of malignant lymphoma.

Lymphoid tumor (malignant lymphoma) of bulbar

conjunctiva.

Tumor involves inferior bulbar and forniceal

conjunctiva

(a)Anterior epibulbar extension of a deeper orbital

lymphoma.

(b)The computed tomography (CT) scan reveals a

large molding soft tissue mass tracking along the

medial orbit and extending onto the epibulbar

surface of the LE.

(a)Bilateral lymphoid lesions of the preseptal

portion of the eyelid. On palpation, the lesions had

a doughy consistency.

(b) CT scan demonstrates masses involving the

eyelids and anterior orbit. The clinical examination

is therefore important in the correct interpretation

of these findings.

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Differential diagnosis of orbital lymphoma

Idiopathic inflammatory pseudotumor

Orbital lymphoid hyperplasia

Orbital sarcoidosis

Wegener granulomatosis

Chronic dacryoadenitis.

Lymphoma of the lacrimal gland Painless mass

Characteristic salmon-colored mass seen in the

superolateral cul-de-sac,

Often fixed to the orbital rim and is rubbery

Radiographic appearance of the bone is usually normal

CT scan a homogeneous consistency with indistinct

borders

Tendency to mold into the contour of the lacrimal fossa

and the surrounding bony contour.

Bilateral painless enlargement of the lacrimal glands leading to mechanical ptosis.

Intraoperative photo shows the enlarged lacrimal gland.

After chemotherapy for systemic lymphoma.`

Fish flesh appearance

lymphoma

Conjunctiva Lacrimal glandTend to be more

benign ,better long-term prognosis

Those that extend into the orbit tend to be more malignant.

Remain localized in 90% of cases

Appear as a diffuse vertical expansion of the gland,

Mold to both the globe and orbital bone

No bony fossa erosion.

Conjunctival lymphoid ‘salmon-patch’ lesion. This

lymphoid tissue is located within the substantia propria

of the conjunctiva and is freely mobile over the

underlying tunics.

NON HODGKINS B CELL LYMPHOMAS

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Subtypes of B-cell nonHodgkin's malignant lymphoma—1. Extranodal B-cell marginal zone

lymphoma, 2. Follicle center cell lymphoma,3. Small lymphocytic lymphoma, 4. Lymphoplasmacytoid lymphoma, 5. Large cell lymphoma, 6. Mantle cell lymphoma,7. Burkitt's lymphoma

1. EXTRANODAL B-CELL MARGINAL ZONE LYMPHOMA

Most common type

Both conjunctival and lacrimal

gland MALT contribute

lysozyme to the tear film.

Chlamydia psittaci is

associated with ocular adnexal

mucosa-associated lymphoid

tissue (MALT) lymphoma

FOLLICULAR LYMPHOMA

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• Is relatively rare

• Middle-aged to elderly

• Females

• Relapses are frequent

• Long-term survival: favorable

JAMA Ophthalmol. doi:10.1001/jamaophthalmol.2014.376Published online April 24, 2014.

, A uniform population ofsmall cells (centrocytes) with irregular nuclei (arrows) consistentwith a grade 1 follicular lymphoma

follicles express CD10,

B CELL-CHRONIC LYMPHOCYTIC LEUKEMIASMALL LYMPHOCYTIC LYMPHOMA

Predominantly a disease of the elderly

Present with leukemia involving the orbit

Relatively indolent disease, but it is virtually

incurable with current therapy

May progress to a higher grade large cell

lymphoma (richter transformation).

LYMPHOPLASMACYTOID LYMPHOMA Occurs in elderly

Paraproteinemia is common

Hyperviscosity state

The optic nerve can be

invaded

Papilloedema from CNS

invasion

Resembles lymphoma in its

diffuse infiltration into

lymphoid tissues.

Bone marrow Biopsy:

characteristic mixture of

small lymphoid cells with

various degrees of plasma

cell differentiation.

PLASMA CELL TUMORS Tumors of mature B cells Secrete monoclonal immunoglobulin detected

as the M-spike on serum electrophoresis, associated with high urine and blood content of immunoglobulin.

Light chain fragments excreted in the urine are known as Bence Jones protein.

Multiple myeloma Prototypic systemic plasma cell tumor

Occurs in the elderly, more commonly men

Multiple masses of plasma cells disseminated throughout

the skeletal system and soft tissue.

Extraskeletal metastases in 70% of cases, either by

hematogenous spread or by direct extension.

Metastasize to the kidney, adrenal gland, heart, and liver

Punched-out lesions of the skull and vertebral fractures.

LARGE CELL LYMPHOMA

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• Worst prognosis for survival.

• Death occurs within 2 years of

diagnosis JAMA Ophthalmol. doi:10.1001/jamaophthalmol.2014.4644Published online November 13, 2014.

High Ki-67proliferative index exceeding 90%(yellow arrowhead) (originalmagnification ×400).

Burkitt’s lymphoma

A rare tumor

Originally described

in africa.

Most common in

children

Comprising 90% of

pediatric lymphomas

in endemic regions

and one third of

nonendemic pediatric

lymphomas..

•In the orbit, it

typically originates

from the maxillary

marrow space.

•Rapid tumor growth

in the face, with a

doubling time of 3

days

•Tumor of monstrous

proportion in 2 to 4

weeks

"starry sky“ appearance.

B, At high power, -monotonous appearance

Management of Burkitts lymphomaChemotherapy regimens based on cyclophosphamide,

doxorubicin, vincristine, and methotrexate.

Prognosis depends on the volume of disease at

presentation,

If the disease is localized, it can be surgically debulked.

Fifty percent of tumors recur, commonly in the

meninges.

Aggressive disease with meningeal invasion -

chemotherapy with bone marrow transplant.

Mantle cell lymphoma

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A, At low power, neoplastic lymphoid cells surround a

small, atrophic germinal center, exhibiting mantle zone

pattern of growth.

B, High-power view shows a homogeneous population of

small lymphoid cells with somewhat irregular nuclear

outlines, condensed chromatin, and scant cytoplasm.

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HODGKINS LYMPHOMA

HODGKIN'S LYMPHOMA

30% of all systemic

lymphomas,

Is rare in the orbital soft

tissues and lacrimal

gland, generally

Occurs late in the

patients with

widespread systemic

disease.

Eyelid involvement and tissue necrosis.

mixed cellularity type. diagnostic, binucleate Reed-Sternberg cell

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T CELL LYMPHOMAS

T-CELL LYMPHOMA

Rare

Usually occurs during the

late stage of systemic

disease ,or

As a manifestation of

mycosis fungoides.

Only one case of primary t-

cell lymphoma in the orbit

has been described.

(a)T-cell lymphoma limited to the eyelid with

ulceration.

(b)The histopathologic features include the

Pautrier-like microabscess

(a and b) Courtesy of Seymour Brownstein,

MD.

Intra ocular lymphoma

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Subtypes of Intra ocular involvement

Primary Central Nervous System

Lymphoma (PCNSL)

Primary Uveal Lymphoma

Metastatic Uveal Lymphoma

Secondary Uveal Lymphoma

Hodgkin’s Lymphoma.

PRIMARY INTRAOCULAR LYMPHOMA

Primary vitreoretinal lymphoma

Vitreous cells and

Geographical subretinal pigment epithelial infiltrative

masses.

Independent nonmetastatic foci of pcnsl

Primary uveal lymphoma

Diffuse or multifocal creamy yellow choroidal

infiltrates in one or both eyes.

Associated with independent foci of visceral NHL

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Primary CNS Lymphoma (PCNSL) A subset of diffuse large B-cell NHL

Increasing incidence and high mortality

Usually affects elderly and is unilateral or bilateral

Infiltrates the retina, vitreous, or optic nerve head

60-80% cases develop CNS disease

Often masquerades as a chronic uveitis

Typical clinical findings: vitritis and sub-RPE

yellow–creamy infiltrates

Tumor cells in the anterior chamber ~75% of patients.

Cells simulate iridocyclitis and form a pseudohypopyon.

20anterior segment changes :

Neovascularization of the iris

Neovascularization of the iridocorneal angle

Possible glaucoma.

In rare circumstances, PCNSLO can form a mass in the

iris or angle.

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Primary vitreoretinal lymphoma.

Typical geographical subretinal pigment epithelial lesion with relatively few vitreous cells.

Posterior segment : vitreous cells are a typical finding

Fundus :low-lying, yellow-to-white mass deep to the

sensory retina.

Single or multiple, confluent or discrete.

May appear as multiple punctate lesions.

Infiltrative and involve all layers of the retina.

PCNSLO : increased frequency in immunosuppressed

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Classical pathological findings: atypical

lymphoid cells between the RPE and Bruch's

membrane, with monoclonality demonstrating

IgH (for B-cell) or TCR (for T-cell) gene

rearrangement

Cytokines: elevation of IL-10 levels in the

vitreous (for B-cell PIOL

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Gross photograph of enucleated globe with PCNSL, revealing retinal thickening, hemorrhage, and RPE involvement

large neoplastic cells with necrosis

Vitreous cytology showing large neoplastic cells

Retinal hemorrhage is rarely seen.

Deep infiltrates can give rise to exudative

retinal detachment.

If chorioretinal lesions regress, scarring and

atrophy of the retinal pigment epithelium may

be the only remaining fundus findings.

Optic neuropathy may also be a feature

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PCNSL involving vitreous and subretinal space

Fluorescein angiogram of left eye during laminar flow phase, revealing early hypofluorescence of lesions noted in A.

Fluorescein angiogram of same eye after 6 minutes, revealing intense staining of infiltrates.

Primary uveal lymphoma.

Diffuse, creamy uveal infiltration with focal nodular accentuation inferotemporal to macula.

DIFFERENTIAL DIAGNOSISPRIMARY VITREORETINAL LYMPHOMA PRIMARY UVEAL

LYMPHOMA  Chronic Idiopathic Vitritis   Vitiliginous Choroiditis    Vitreous Amyloidosis    Metastatic Carcinoma    Cytomegalovirus

Retinitis. Pars Planitis

(Intermediate Uveitis)   Leukemic Intraocular Infiltration 

Metastatic carcinoma   Pneumocystis carinii

choroiditis      Benign reactive lymphoid Hyperplasia   Posterior scleritis , Harada’s disease    Bilateral diffuse uveal

melanocytic proliferation associated with systemic carcinoma

Metastatic systemic lymphoma

Confined to the uvea (esp: the choroid).

Compared with PCNSLO, metastatic systemic

lymphomas are

much less prevalent

have a better prognosis

less likely to create a diagnostic dilemma.

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Diagnosis High index of suspicion Radiologic imaging Histologic analysis

Vitreous biopsy Flow cytometrySubretinal aspiration Retinal biopsy

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Laboratory studies Complete blood count (CBC) with

differential

Serum immunoprotein

electrophoresis

Rapid plasma reagin (RPR)

screening

Erythrocyte sedimentation rate

(ESR)

Fluorescent treponemal antibody

absorption (fta-abs) test

Toxoplasma titers

.

Antinuclear antibodies (ANA) test

Rheumatoid factor

Angiotensin-converting enzyme

(ACE)

Cytomegalovirus (CMV) titers

A tuberculosis skin test is

advisable.

The serum lactate dehydrogenase

(LDH)

Enzyme-linked immunosorbent

assay (ELISA) for HIV is also

recommended

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B-scan ultrasonography

intraocular mass.

retinal detachment.

CT and MRI:

low sensitivity for intraocular lymphoma

do not facilitate differentiating the diagnosis against uveitis

or ocular melanoma

Imaging of the CNS with contrast to look for lesions

elsewhere.

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Lumbar puncture : if CNS lymphoma is suspected.

Bone marrow aspiration for staging systemic

lymphomas.

CT scans of the chest and abdomen to rule out

retroperitoneal lymphoma.

Bone scans may also be done

Vitreous biopsy

Retinal biopsy

Orbital biopsy

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Because of the fragility of neoplastic lymphocytes, a specimen

may contain numerous abnormal-appearing but uninterruptable

cells.

Molecular analysis : adjuncts to cytology for establishing the

diagnosis of PCNSLO.

immunoglobulin gene rearrangements and

ocular cytokine levels

elevated interleukin (IL)–10

IL-10–to–IL-6 ratio greater than 1.0, are helpful

CDR3 polymorphism analysis to confirm clonality.

DIAGNOSIS OF LYMPHOMA

CT helps in localizing orbital involvement

Biopsy can provide the definitive diagnosis.

Histopathology - cornerstone of the diagnostic

process.

Molecular pathology -to detect monoclonal gene

Cytogenetic abnormalities such as chromosomal

translocations or karyotypic abnormalities

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TreatmentRadiotherapy

RT + chemotherapy in the presence of central

nervous system involvement.

For non-Hodgkin's lymphoma, chemotherapy

involves the use of

iv Cyclophosphamide 750mg/m2 on days 1 and 8,

iv Adriamycin 45mg/m2 on days 1 and 8,

iv Vincristine 1.5mg/m2 on days 1 and 8 and

oral Prednisolone 20mg 8 hourly for 10days.

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For Hodgkin's lymphoma, chemotherapy involves the

use of ABVD regimen

iv Adriamycin 25mg/m2 on days 1and15;

iv Bleomycin 10U/m2 on days 1and15;

iv Vinblastine 6mg/m2 on days 1and15 and

iv Dacarbazine 375mg/m2 on days 1and15).

High dose methotrexate and Leucovorin rescue may also

be used for ocular lymphoma.

Multimodality therapy

Boosted radiation dose (5000-10,000 cGy) to

the spinal cord and

Intrathecal methotrexate,

Vision can be improved and life can be

prolonged, with some patients alive at 9

years after treatment.

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Multiagent primary chemotherapyDesigned to reduce radiation-associated

cognitive defects

Can occur in up to 40% of patients older

than 50 years.

Methotrexate and procarbazine, vincristine,

thiotepa, or both vincristine and cytarabine.

Complete remission for long as 30 months

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Lymphoid tumors of the conjunctiva Traditionally treated with local radiation

therapy.

Cryotherapy suggested Fewer ocular and systemic complications and

lower cost

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Primary orbital lymphomaRadiotherapy alone is highly effective Bilateral orbital disease with no systemic disease,

is not an indication for chemotherapy.

High-grade tumors may require up to 4000 cGy.shielding of the globe (lens-sparing technique) is to

minimize ocular complications

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,

In some cases, combining such systemic therapy with local radiation treatment is beneficial.

After radiotherapy, local control was achieved in 97-100% of patients.

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Monoclonal antibody (mAb)Lymphomas respond well to mAb therapy,

Rituximab,

Ibritumomab

Epratuzumab

IV rituximab –for low-grade lymphoma showed

good results.

Antiangiogenic drugs – use of thalidomide is in

study04/15/23

ReferencesAlbert & Jakobiec's principles & practice of

ophthalmologyYanoff & Duker: ophthalmology, 3rd ed.2008,ch 8.4Robbins and Cotran Pathologic Basis of Disease 7th

ed 2005, pg 667 - 690JAMA ophthalmol.

Doi:10.1001/jamaophthalmol.2014.4644 published online november 13, 2014.

JAMA ophthalmol. Doi:10.1001/jamaophthalmol.2014.376 published online april 24, 2014

AAO Textbook of Ophthalmic Pathology & Intraocular tumors.2011-2012, pg 323-326

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