Yong Meng Hsien Lecturer & Ophthalmologist, UKM & HCTM, Malaysia yongmenghsien@ppukm.ukm.edu.my Last edited: Feb 202

1. Systemic Malignancy
& Eyes
Dr Yong Meng Hsien
Lecturer & Ophthalmologist, UKM & HCTM
yongmenghsien@ppukm.ukm.edu.my
Last edited: Feb 2022

2. Discussion:
• Systemic malignancy  ophthalmic complaint  general
approach and considerations
• Ophthalmic conditions  need TRO underlying malignancy
• Metastasis & Infiltration (lymphoma & leukemia)
• Orbital
• Intraocular
• Neuroopthalmic
• Adult VS paeds
• Metastasis
• Primary breast VS lung VS prostate Ca- the difference
• General approach for DDx, workup and treatment
• Treatment related ocular complications
• ChemoT, RadioT, Newer agents
• Paraneoplastic

3. Approach: Cancer + Ophthalmic Complaint
• BOV
• Anatomy: cornea & ocular surface – optical media – retina &
ON & uveal – visual pathway
• Diplopia
• Anatomy: EOM – NMJ – CN – Brainstem – Cerebral cortex
• Pain & redness & swelling
• Characterization of symptoms
• Ocular VS Orbital
• Infection VS Inflammation

4. Classical Pain @Eye
• Periocular pain with headache n&v + seeing halo then
BOV  acute glaucoma
• Severe dull deep boring pain, unable to sleep and
worsened with eye movement  scleritis
• Sudden sharp aching pain on eye blinking,
+photophobia +tearing, and relieved with eye closure
 corneal erosion
• Mild-mod eye pain on movement but ++ BOV  optic
neuritis
• Pain at temporal forehead with tender on touch 
giant cell artertis

5. Eye problem @systemic cancer
• Ophthalmic (ocular & orbital) metastasis
• Ophthalmic (ocular & orbital) infiltration (lymphoma &
leukemia)
• Orbital apex
• CNS cancer involving ocular motility, visual pathway, ICP
• Infection (immunocompromised)
• Hematological d/o (hyperviscosity, anemia,
thrombocytopenia)  vascular event (ocular or CNS)
• Treatment complication (chemoT/radioT)
• Phakomatoses (association)
• Paraneoplastic syndrome
• MEN2B

6. Malignancy/Tumour/Cancer @Eye
• Primary ophthalmic
• Secondary: metastasis or direct extension
• Infiltration lymphoma/lymphoid or leukemia
• Phakomatoses
• Paraneoplastic tumour
• Endocrine neoplasia/MEN
• CNS malignancy involving optic pathway, ocular
motility, or high ICP

8. Orbital Tumour
• Anatomical
• Eyelid
• Lacrimal
• Vascular
• Nerve
• Lymphatic
• Soft tissue/cyst
• Hamartoma VS Choristoma
• Primary VS Secondary
• DDX:
• Infiltration: lymphoma/leukemia
• Infection: cellulitis, dacryoadenitis/cystitis, TB/fungal
• Inflammation: TED/vasculitis/sarcoid/IgG4/pseudotumour

9. Orbital Tumour & Proptosis
• Axial/non axial (dystopia/diplopia)
• Orbital apex syndrome/ON/RAPD
• Corneal exposure K
• Paeds: amblyopia/refractive error/astig
• Origin:
– ON/vascular/lacrimal/eyelid/embryonal
– mets/lymphoma/leukemia
• Association
– Systemic/syndrome/phacomatoses
• DDx:
– VEINS

10. Secondary Orbital Tumour
- Local Spread/Metastasis -
Paeds
• Neuroblastoma (26%)
• 1`- neck/abd/mediastinum
• SSx: BL ecchymotic
proptosis, congenital
Horner/heterochromica
• Mx: chemoT > radioT, <1yo
90% survive, >1yo 10%
• Nephroblastoma
•Leukemia >ALL
* more to orbit!
•ON Glioma
Adults
•Breast > lung >prostate
• palliative/radioT
*more to choroid!
•Eyelid (SCC/BCC/SGC)
•Choroidal melanoma
•Sinus ca/NPC (SCC)
•ON sheath meningioma

11. Lacrimal Tumour
• Primary
– benign
• Epithelial: pleomorphic adenoma
• Non epithelial: benign proliferative lymphoid hyperplasia
– malignant
• Epithelial
– adenocystic Ca
– pleomorphic adenoCa (malignant mixed tumour)
– sq cell mucoepidermoid Ca
• Non epithelial: lymphoma
• Secondary: direct adjacent vs distant (lymphoma)
• DDX: TB/fungal/Inflam (Sarcoidosis)/CTD (Wegener)

12. Malignant Lacrimal Tumour
Pleomorphic AdenoCa Adenoid Cystic Ca Lymphoma
Age 20-50s >F 40-50s >F >50s
Onset slow >1yr faster <1yr Insidious/acute on
chronic
Pain - + (perineural spread) -
Location UL UL UL/+-BL (17%)
CT Pseudocapsule
Round/smooth @fossa
Bone indentation/
pressure changes
No capsule
Calcification, bone
erosion, nerve invasion
Diffuse (both
orbital/palpebral)
Molded to shape og
globe
Systemic TAP LN
Mx Incisional Bx → Excision
+ radioT → exenteration
Incisional Bx  excision
 exenteration/chemo-
radio
Bx/chemo/radio
Risk Long standing adenoma,
prev incomplete excision
Histo: worse Basaloid >
Cribriform

14. Ophthalmic Metastasis
• Intraocular > orbit
• Orbit: lids, conjunctiva or orbital soft tissue
• Intraocular: uvea > retina or OD
• Uvea: Choroid > iris & CB
• ON: swollen optic disc
• Uveitis: hypopyon (white eye, shifting), panU
• Secondary tumour/direct extension VS metastasis
(hematogenous)
• Important of eye assessment:
• first presentation before tumour
• ocular Rx for vision threatening
• monitor response of systemic Rx

15. Primary Malignancy
• Breast
• > bilateral, multifocal
• > a/w brain mets
• metastatic scirrhous breast cancer with enophthalmos >proptosis
(desmoplasia/fibrosis/contraction)
• Lung
• > undiagnosed primary (CXR!)
• > least favourable prognosis
• > unilateral, unifocal +- painful
• Prostate Mets to orbit > uveal
• Orbit > bone mets
• Secondary tumour/direct extension
• Orbit  ocular
• Conjunctival SCC > conjunctival melanoma & eyelid BCC
• Conjunctival SCC: mucoepidermoid carcinoma or spindle cell variant.
• Adnexal  orbit
• Eyelid/conj tumours
• Intraocular  orbit
• RB & uveal melanoma
• Adjacent
• Paranasal sinuses: Maxillary & ethmoid sinus carcinoma
• Nasopharyngeal: carcinoma, angiofibroma
• Cranial cavity: meningioma, meningoencephalocele

16. Orbital VS Uveal Metastasis
• Similarity
• Mostly known Ca, 10-20% unknown
• Can be asymptomatic (esp uveal)
• Hematogenous spread
• Primary > breast & lung, Ca > melanoma/sarcoma
• Difference
• Presentation & different ser of DDx
• Primary prostate >orbit
• Bilateral @uveal (esp breast mets) >> orbit (rare)
• Orbital mets can considers FNAC/ tissue biopsy (even known Ca) VS uveal mets
• Orbital mets > complete removal if well circumscribed tumour
• DDx orbital mets: benign orbital tumors, lymphomas/leukemia, pseudotumor,
infection/inflam
• DDx uveal mets: ifx/inflame/retinitis choroiditis granuloma, primary uveal tumour
e.g. nevus/melanoma/hemangioma/osteoma, sclerochoroidal calcification,
RRD/choroidal detachment/scleritis, CNV/SRH-fibrosis, CSCR, VKH

17. Orbital Metastasis
• 1–13% of all orbital tumors, 2–5% of patients with systemic malignancies
• Orbital symptoms- 50% +symptoms, orbit bone/tissue/EOM/ON, eyelids
• Red flag: recurrent chalazion/nodules, fleshy mass/recurrent pterygium
• Location: more lateral n anterior orbit, opposite I M SLow
• Primary: breast >lung > prostate, Ca>melanoma
• prostate Ca > bone mets
• breast Ca and melanoma > orbital fat and muscle mets
• Ix: Imaging/MRI, FNAC, surgical biopsy (incisional/excisional)
• MRI: vs orbital fat, hypointensity on T1 hyperintensity on T2 w enhancement.
• +- bone erosion
• rarely cystic and calcific changes
• Rx: radiation for symptoms (meaningful option)
• > debulking, chemoT
• 20–40Gy of 1–2 weeks

18. Choroidal Metastasis
• Choroid: > macular or perimacular region
• creamy yellow (+-gray/white), elevated mass deep to the retina in the choroid
• SRD +/- flat & ill defined mass (flat metastasis)
• Leopard skin (RPE pigment clumps)
• +-dilated peribulbar vessel @same area
• VS Melanoma
• Thickness: Mets (esp breast ca) 2-3mm < melanoma (5.5mm)
• Morphology: Mets > yellow/homogenous, <RPE disturbance
• B scan: Mets > echogenic/dense & low height:base (>flat), melanoma echolucent/acoustic
hollowness
• A scan (reflectivity): Mets > high
• Rx
• Factors: symptoms, systemic status, lesion (location/laterality/number)
• observe if asymptomatic w known primary & controlled
• multifocal/bilateral- plaque RT (2days), EBRT (daily radiation for four weeks)
• unifocal- plaque RT
• new: breast CA hormonal therapy with the new aromatase inhibitors

19. Choroidal Metastasis- Workup
• 1st sign of systemic malignancy in 1/3 cases
• 10% of cancer +uvea mets (breast & lung)
• Photo: wide-field
• A- and B-scan: echogenic/acoustic solid, ill defined +- lobulated,
irregular higher reflectivity, SRD
• AF: tumour hypo, SRF hyper, lipofusin deposit hyper
• OCT: macular involvement/SRF, lumpy bumpy choroidal surface (EDI),
choriocapillaris compression, and photoreceptor loss
• FFA: rule out simulating lesions
• Mets: >hypoF @early FFA  later diffuse patchy hyperF (multifocal leaks in the
RPE with SRD)
• Melanoma > double circulation pattern and prominent early choroidal filling
• FNAC & tissue biopsy if unsure

20. Iris & CB metastasis
• white or gray-white gelatinous nodules
• iridocyclitis
• secondary glaucoma
• rubeosis iridis
• hyphema
• irregular pupil

21. ON metastasis
• parenchyma or the optic nerve sheath
• edema ONH
• decreased vision
• visual field defects

22. Retinal Metastasis
• very rare
• white, noncohesive lesions, CWS-like >perivascular
• + secondary vitreous seeding of tumor cells (DDx
retinitis)

23. Paediatric Metastasis
• Orbital mets
• Neuroblastoma (most)
• Esp. adrenal
• Rapid proptosis (UL/BL) with eyelid ecchymosis
• Orbital CT (mass + bone destruction) + abd CT (adrena)
• Others: Wilms tumor (nephroblastoma) & Ewing
sarcoma

25. Leukemia & Lymphoma
• Leukemia ophthalmic involvement: “primary” or direct leukemic infltration, and “secondary” or
indirect involvement. Direct leukemic infltration 3 patterns: masquerade uveitis, OD/ON +- CN,
orbit.
• Rx systemic vs local:
• - systemic chemotherapy and biological treatments, irradiation
• - intravitreal injections of dexamethasone, anti-VEGF, or methotrexate (MTX)
•
• Primary vitreoretinal lymphoma (PVRL) is closely related to primary central nervous system
lymphoma (PCNSL), and is an aggressive malignancy. In contrast, primary uveal lymphomas are
more typically indolent, similar to ocular adnexal or orbital lymphomas in terms of
aggressiveness.
• diffuse large B cell lymphoma (DLBCL), the subtype that is most commonly found in PVRL
• extranodal marginal zone lymphomas (EZML), more typical of orbital lymphoma, as well as
many uveal lymphoma

26. Lymphoproliferative D/O
• Lymphoid hyperplasia (benign) (low grade lymphoma)
• Uveal, conj, orbit
• Lymphoma
• Histiocytic d/o
• Xanthogranuloma
• Plasma cell tumour (MM/plasmacytoma)
• Lymphoepithelial infiltration (Sjogren/Mikulicz)

27. Ophthalmic Lymphoma
Types
• Ocular adnexal/orbital lymphoma (20% of orbital tumour)
– Orbit
– Lids
– Lacrimal gland (50%, >a/w systemic lymphoma)
– Conjunctiva
• Intraocular lymphoma
– Uveal (rare/>secondary/mets) = systemic/visceral/nodal lymphoma
– Vitreo-retina (>primary/CNS lymphoma) = primary intraocular/large cell/retinal lymphoma
General
• PathoP: Infection/inflammation-Mutation Model (IMM)
• SSx: slow/no pain/no symptoms
• Orbital- 30% before 30% after systemic lymphoma (need systemic workup)
• Ocular- primary VR CNS lymphoma (need LP/brain imaging & systemic workup)
• Biopsy: flow cytometry, immunohistochemistry, cell surface marker, PCR
• CD 20 for B cell, CD 3 for T cell
• IL10-IL 6 ratio)
• steroid Rx will change the HPE of lymphoma

28. Orbital Lymphoma
• Intro: 20% of orbital tumour
• Risk: age/chemical exposure/autoimmune dz (chronic)
• Systemic lymphoma- 30% prior & 30% aft
• +- simultaneous conj + uveal lymphoma
• Key feature: UL/painless/progress (BL 17%)
• Orbita: ptosis/proptosis/EOM/diplopia, mass >anterior/lateral orbit
• Eyelid: S-shaped/firm rubbery mass
• a. B-cell lymphoma--firm subcutaneous mass
• T-cell lymphoma--more superficial (mycosis fungoides)
• Conj: salmon patch
• Uveal: infiltration/uveitis
• Ix: (staging/CT/Bx) systemic!
• Staging: blood/CXR/BMAT/neck TAP CT or PET
• CT scan mold to structure (rarely EOM/ON d/o, if +invasion=high grade)
• Bx: fresh sample (cell surface marker/flow cytometry/PCR/microscope)
• FNAC, small for excisional, large for incisional
• Mx:
• Orbital only: radioT +-25Gy (+- Rituximab)
• If systemic: chemo/radioT (+-debulking)
• a. 1500-2000 cGy for benign lesion
• b. 3000-3500 cGy for atypical or malignant

29. Orbital/Adnexal Lymphoma
5keys
• Extranodal
• Non Hodgkin
• B cell (95%)
• Bone marrow derived/Homing mechanism
• Multifocal (not metastasis)
5 common types
• Extranodal marginal zone EMZL (most)
• Diffuse large cell DLCL (high grade)
• Follicular FL
• Mantle cell ML
• Small cell/lymphoplasmatic LPL (high grade)
* Other class (REAL)- MALT/small cell/follicular/high grade (large
cell/Burkitt/lymphoplastic)

30. Intraocular Lymphoma
• Types/location
• VR >primary & a/w CNS lymphoma
• >common/aggressive/non Hodgkin/extranodal/B cell/large cell)
• If 2nd to VR > Hodgkin’s type (rare)/>chorioretinitis
• Uvea (rare) > 2nd/metastatic dz (similar to adnexal lymphoma)
• Primary VR lymphoma
• EpiD: >50/UL  BL (most)/a/w immunosuppression
• SSx: PU/PanU, white retinitis >subretinal
• + Cx (RPE clump/vasculitis/RVO/RAO/RD/OD, but rarely CMO)
• ++ dense vitritis
• +- AC reaction (+white eye hypopyon)
• +- CNS SSx (brain/spine/meningitis)
• Ix (eye): FFA (leopard skin), Bscan (SR placoid/nodules), vitreous/TPPV tap/Bx, subretinal Bx
• Ix (sys): LP, MRI brain/orbit (MUST)
• Mx: (depend laterality/CNS involvement)
• Ocular: IVT MTX/radioT (EBRT) if UL, IV MTX/IVT MTX/radioT if BL (IV poor
penetration/>recurrence)
• Systemic/CNS: IV+-intrathecal MTX/chemoT
• New: biological agent (rituximab- Intravitreal or systemic)
• Prognosis: poor

31. Intraocular Uveal Lymphoma
• Amelanotic, amelanotic yellow uveal
(iris/CB/choroid) stromal mass
• +- a/w orbital/conj lymphoma
• +- overlap with primary VR lymphoma (if advanced)
• DDx: metastasis , birdshot choroiditis, or
sarcoidosis
• Rx
• Partial response to steroid
• Responds well to low doses of radiotherapy (1500-2000
cGy)
• Systemic for chemoT

32. Vitreous biopsy- Lymphoma
• Dry PPV/undiluted vitreous or subretinal fluid
• cytopathology including immunohistochemical
studies for subclassification of the cells, flow
cytometry, and polymerase chain reaction (PCR)
and fluorescence in situ hybridization (FISH)
analysis for gene rearrangements and the ratio of
interleukin-10 (IL-10) to IL-6
• Specimens that reveal malignant lymphocytic cells
establish the diagnosis and evaluation of cell
surface markers may allow for subclassification of
the tumor.

33. Leukemia & Eye
• 40-80% eye involvement
• Retina (most)
• Leukemic retinopathy
• > vasculopathy: hrge (IR/SH), CWS, HE, roth
• < infiltrate: yellow deposit (R/SR), gray white streak @perivascular
• Uvea
• Choroidal infiltrate: thickening (subtle), SRF
• Iris: thickening +- nodule
• White eye/pseudo-hypopyon (leukemic cells)
• ON infiltration  emergency
• Orbital: soft tissue >lat/medial (+-temporal fossa swelling)
• =granulocytic sarcomas or chloromas
• Ix: systemic, CNS/LP, +- diagnostic PPV
• Rx: chemo (systemic, IT > ON), radiation > orbit/uveal

34. ChemoT & Eye
• Temporal relationship  chronological correlation
• Bone marrow suppression
• Infection
• Hematological d/o: anemia thrombocytopenia
• Tamoxifen for breast Ca
• Estrogen dependent
• Keratopathy & retinopathy (+-deposit), cataract
• Imatinib for leukemia
• Philadelphia chromosome positive (Ph+) CML/ALL
• Fluid retention with periorbital edema
• Rituximab for lymphoma
• B cell NHK lymphoma, CD20 Ag Ab
• Min ocular SE, conjunctivitits

35. RadiationT & Eye
• Cataract
• radiation retinopathy
• radiation optic neuropathy.

36. Others & Newer agents
• breast Ca with mets: hormonal therapy with the
new aromatase inhibitors
• Primary intraocular lymphoma: intravitreal
rituximab
• Graft-vs-host disease: BM transplantation

38. Calcification
Intraocular
• RB
• Choroidal osteoma
• Choroidal hemangioma
• ON meningioma
• Osseous choristoma
• Phthisical
Intracranial
• SWS
• TSC
• Toxoplasmosis
• Craniopharyngioma

39. Multiple endocrine neoplasia (MEN) type 2B
• AD (chr 10q11)
• medullary carcinoma of the thyroid gland,
pheochromocytoma, and mucosal neuromas
• marfanoid habitus, thickened corneal nerves,
conjunctival and eyelid neuromas and
keratoconjunctivitis sicca

40. Paraneoplastic Syndrome (PNS)
• Def: cancer-related SSx
• not related to mass effect but
• humoral (hormone/cytokine) from tumour, or
• immune reaction to tumour
• Common sources: lung, breast, ovaries, lymphoma
• Types:
• Neurological: Lambert Eaton/MG (small cell lung ca), myositis,
spinal cord, CNS
• Hematological: low/high RBC/Hb/hypercoagulopathy
• Endocrine: high Ca/ACTH-Cushing/ADH-SIADH/insulin-hypoG/
aldosterone/carcinoid (serotonin)
• Muco-cutaneous
• Ocular: retinopathy (CAR/MAR)
• Ix: autoimmune Ab (anti-Hu/Ri/Yo/Ma/Amphiphysin/CVS)
from IMR, whole body CT scan/PET

41. Visual paraneoplastic syndromes
• Circulating antibody affecting retinal protein (cross
reaction with tumour antigen)
• The first affects photoreceptors, the second is
thought to affect bipolar cell function, and the third
targets the uveal tract
• carcinoma-associated retinopathy
• melanoma-associated retinopathy
• bilateral diffuse melanocytic uveal proliferation
• paraneoplastic optic neuropathy (PON)

42. Paraneoplastic retinopathy
CAR (cancer-associated retinopathy)
• Ab against recoverin/retinal protein
• Peripheral + central visual loss (rapid/progress)
• Arterial narrowing with only min/no pigment
• ERG- Extinguished
MAR (melanoma-associated retinopathy)
• ERG- negative waveform
Others
• Autoimmnue retinopathy
• BDUMP (BL diffuse uveal melanocytic proliferation)-
choroidal lesion + ERD + PSCC + iris/CB cyst
• Acute exudative polymorphous vitelliform maculopathy

43. Histocytosis X/Langerhans cell
• Intro: abn dendritic histiocyte/mononuclear phacocyte
• EpiD: >peads (5-10yo)
• SSx:
• Spectrum of severity- spontaneous resolution 
dissemination/death
• Orbital inflam: relapsing/lytic bone lesion (orbit/sphenoid
wing)/proptosis (sup temporal)
• Mx: Bx  debulking/steroid injection/low dose radioT 
chemoT (if systemic)
• Prognosis: worse if <2yo (50% survive), >2yo (90% survive)
• Variant: juvenile xanthogranuloma (non Langerhans
histiocytic lesion/self limit/steroid sensitive)

44. Xanthogranuloma
• Intro: systemic (+orbital) lymphoid tumour
• 4 syndromes
• Necrobiotic X
• Adult onset X
• Adult onset asthma with periocular X
• Erdheim-Chester dz (ECD: @adult/worse)
• Variant: juvenile xanthogranuloma
• Systemic: paraproteinemia/MM, LN, fibrosclerosis
of pleural/fascial