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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06/14/15
Ocular lymphoma

 Orbit is an extranodal site

 Depending on the site of involvement,

Orbital

Adnexal

Intraocular

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Distribution of common lymphoproliferative lesions of the orbit.
Ocular manifestations
 Frequently 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.
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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

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 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.
Differential diagnosis of orbital lymphoma

Idiopathic inflammatory pseudotumor

Orbital lymphoid hyperplasia

Orbital sarcoidosis

Wegener granulomatosis

Chronic dacryoadenitis.

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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.

Fish flesh appearan

After chemotherapy for systemic lymphoma.`

lymphoma
Conjunctiva
 Tend 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
Lacrimal gland
 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
• Is relatively rare
• Middle-aged to elderly
• Females
• Relapses are frequent
• Long-term survival: favorable

, A uniform population of follicles

small cells (centrocytes) express
with irregular nuclei CD10,
(arrows) consistent
with a grade 1 follicular
lymphoma
JAMA Ophthalmol. doi:10.1001/jamaophthalmol.2014.376
Published online April 24, 2014. 06/14/15
B CELL-CHRONIC LYMPHOCYTIC LEUKEMIA
SMALL 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 Bone marrow Biopsy:

 Resembles lymphoma in its diffuse characteristic mixture of

small lymphoid cells with
infiltration into lymphoid tissues. 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

High Ki-67
proliferative
index
exceeding
90%
(yellow
arrowhead)
(original
magnificatio
n ×400).
• Worst prognosis for survival.
• Death occurs within 2 years of
diagnosis JAMA Ophthalmol. doi:10.1001/jamaophthalmol.2014.4644
Published online November 13, 2014. 06/14/15
Burkitt’s lymphoma
•A
Inrare
the orbit,
tumorit typically
originates
Originallyfrom the maxillary
described in africa.
marrow space. in children
Most common
•Rapid
"starry sky“ appearance.
tumor growth in the
 Comprising 90% of pediatric
face, with a doubling time of
lymphomas in endemic
3 days
regions and one third of
•Tumor of monstrous
nonendemic pediatric
proportion in 2 to 4 weeks
lymphomas..
B, At high power, -monotonous
appearance
 Management of Burkitts lymphoma
 Chemotherapy 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

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. 06/14/15
HODGKINS LYMPHOMA

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HODGKIN'S LYMPHOMA

 30% of all systemic

lymphomas,
 Is rare in the orbital soft

tissues and lacrimal gland,

generally
 Occurs late in the patients
mixed cellularity type.
with widespread systemic
diagnostic, binucleate Reed-
Sternberg cell
disease.
Eyelid involvement
and tissue necrosis.
T CELL LYMPHOMAS

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 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

06/14/15
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
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
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 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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Primar y 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

06/14/15
 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

06/14/15
 PCNSL involving vitreous
and subretinal space

Fluorescein angiogram of
Fluorescein angiogram of left eye during same eye after 6 minutes,
laminar flow phase, revealing early revealing intense staining of
hypofluorescence of lesions noted in A. infiltrates.
Primar y uveal lymphoma.

Diffuse, creamy uveal infiltration with focal nodular

accentuation inferotemporal to macula.
 DIFFERENTIAL DIAGNOSIS
PRIMARY
VITREORETINAL PRIMARY UVEAL
LYMPHOMA LYMPHOMA
  Chronic Idiopathic Vitritis  Metastatic carcinoma  
   Vitiliginous Choroiditis      Pneumocystis carinii choroiditis     
 Vitreous Amyloidosis     Benign reactive lymphoid
 Metastatic Carcinoma    Hyperplasia  
 Cytomegalovirus Retinitis.   Posterior scleritis ,
 Pars Planitis (Intermediate   Harada’s disease   

Uveitis)  Bilateral diffuse uveal melanocytic

   Leukemic Intraocular proliferation associated with
systemic carcinoma
Infiltration
 
 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 cytometry
Subretinal aspiration
Retinal biopsy

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 Laboratory studies
 Complete blood count (CBC) with  Antinuclear antibodies (ANA) test

differential  Rheumatoid factor

 Serum immunoprotein electrophoresis  Angiotensin-converting enzyme (ACE)

 Rapid plasma reagin (RPR) screening  Cytomegalovirus (CMV) titers

 Erythrocyte sedimentation rate (ESR)  A tuberculosis skin test is advisable.

 Fluorescent treponemal antibody  The serum lactate dehydrogenase

absorption (fta-abs) test (LDH)
 Toxoplasma titers  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. 06/14/15
 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.

06/14/15
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
Treatment
 Radiotherapy

 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.

06/14/15
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 chemotherapy
Designed 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

06/14/15
Lymphoid tumors of the
conjunctiva
 Traditionally treated with local radiation therapy.

 Cryotherapy suggested
 Fewer ocular and systemic complications and lower cost

06/14/15
Primary orbital lymphoma
 Radiotherapy 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
06/14/15
,

 In some cases, combining such systemic therapy with local

radiation treatment is beneficial.
 After radiotherapy, local control was achieved in 97-100% of
patients. 06/14/15
 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 study

06/14/15
References
 Albert & Jakobiec's principles & practice of ophthalmology
 Yanoff & Duker: ophthalmology, 3rd ed.2008,ch 8.4
 Robbins and Cotran Pathologic Basis of Disease 7th ed 2005, pg
667 - 690
 JAMA 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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THANK YOU