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1/31/2020
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OPHTHALMOLOGYB Y E R S E Y E I N S T I T U T E
PRESENTATION TITLE
Prithvi Mruthyunjaya, MD, MHSAssoc ia te P rofes so r o f Ophtha lmo logyDi rec to r, Ocu lar Onco logy Ser v i ceD i rec to r, V i t reore t i na l Su rgery Fe l lowsh ip
M a r y M . a n d S a s h A .Spencer Center ForVision Research
ACKNOWLEDGEMENTS AND DISCLOSURES
Consultant:• Castle Biosciences, Optos, SPARK, Arix
Biosciences, ClearSight
• Funding from the National Eye Institute (P30-026877), and Research to Prevent Blindness, Inc.
ACKNOWLEDGEMENTS AND DISCLOSURES
P30-026877
OPHTHALMOLOGYB Y E R S E Y E I N S T I T U T E
OCULAR IMPACT OFSYSTEMIC CANCERS
P r i t h v i M r u t h y u n j a y a , M D , M H S
A s s o c i a t e P r o f e s s o r o f O p h t h a l m o l o g y
D i r e c t o r , O c u l a r O n c o l o g y S e r v i c e
D i r e c t o r , V i t r e o r e t i n a l S u r g e r y F e l l o w s h i p
M a r y M . a n d S a s h A .Spencer Center ForVision Research
ACKNOWLEDGEMENTS AND DISCLOSURES
Consultant:• Castle Biosciences, Optos, SPARK, Arix
Biosciences, ClearSight
• Funding from the National Eye Institute (P30-026877), and Research to Prevent Blindness, Inc.
I AM AN OCULAR ONCOLOGIST
Comprehensive care of cancerous, pre-cancerous and simulating conditions in and around the eye
Impact of treatments of systemic cancers on the eye
Spans all specialties in Ophthalmology
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STANFORD OCULAR ONCOLOGY SERVICE
Childhood:• Retinoblastoma
Conjunctival and Iris tumors
Posterior segment• Melanoma• Lymphoma
Ocular complications of systemic cancers
OCULAR IMPACT OF SYSTEMIC CANCERS
Metastatic tumors to the eye• Presentation• Treatment options
Paraneoplastic conditions
Ocular toxicity from systemic therapy
A BRIEF TOUR…
Cornea
Conjunctiva
Iris
Retina
Choroid
Optic NerveCiliary Body
CLINICAL CASE
66 yo Caucasian male with gradual vision loss over 1 year.
Now with choroidal lesion, left eye
PMH• Resected cutaneous melanoma
• 11.6 x 11.7 mm base• 5.18mm height• Low-mid internal reflectivity
METASTATIC SCREEN
Multilobed right kidney mass• 5 X 7 X 4 cm lesion with calcifications and cyst
Needle biopsy• renal cell carcinoma
Laproscopic resection
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OCULAR METASTASES FROM SYSTEMIC CANCER
First reported in 1852 Most common intraocular tumor
• 8% of cancer patient eyes at autopsy 8-30% precedes diagnosis of systemic cancer
• Indicative of Stage IV disease, poor prognosis
Lin and Mruthyunjaya. Int Clin Ophthal 2014 Chen et al. Survey Ophthalmology 2011
WHY THE UVEAL TRACT?
Cornea
Conjunctiva
Iris
Retina
Choroid
Optic NerveCiliary Body
CLINICAL PRESENTATION
Blurred Vision 75% Photopsias 5-
12% Pain 5-14% NO symptoms 9-11%
Pancreatic Adenocarcinoma
Shields et al. 2005
CLINICAL FEATURES
Yellow/white mass94%
Subretinal Fluid73%
Speckled RPE 45%
• “leopard spot”
Bilateral, multifocal Orange color
• Renal cell, thyroid, carcinoid
CHOROIDAL METASTASIS - TESTING
Detailed cancer history Systemic evaluation tailored to
clinical presentationRe-staging in known cancersMRI brain should usually be
performed due to high incidence of CNS lesions (30%)4
TUMOR ORIGINS
Mathis et al. PRER 2019
66%
33%
Cancer status
Known malignancyNo known malignancy
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BREAST CANCER OCULAR METASTASIS
Woman with known stage IV disease Only 3% initial manifestation of breast
CA 16% first metastatic site
• Mean 48 months after 1st diagnosis Treatment (regress+stable)
• ERBT (93%)• Systemic therapy (88%)
Survival after eye mets• 1 year 65%• 5 year 24%
Demirci et al. AJO 2003
LUNG CANCER OCULAR METASTASIS
Men with unknown primary tumor 44% initial manifestation of lung CA
Mean 31 months after diagnosis Treatment (regress+stable)
• Chemotherapy (63%)• ERBT (86%)
Mean survival from ocular met• 12 months
Metastatic papillary thyroid carcinoma to the Iris
Metastatic papillary thyroid carcinoma to the Iris
TREATMENTS FOR OCULAR METASTASES…
Optimizing systemic therapy
Ocular therapy• Photodynamic Therapy• Radiation Therapy• Laser therapy• Anti-VEGF therapy
C H O R O I D A L M E TA S TA S I S - P H O T O D Y N A M I C T H E R A P Y
Long duration infrared ”cold” laser + photosensitizer (verteporfin)
Generates free radicals leading to vasoconstriction, thrombosis, and immune reaction
Initially introduced for therapy of wet-AMD
77-100% reduction in tumor size Mathis et al. PRER 2019
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HISTORY OF PRESENT ILLNESS
71 year old female, referred for retinal lesion in the left eye
Notes transient darkening of peripheral visual field, occasional photopsias for the past few weeks
PAST MEDICAL HISTORY
June-October 2017 - persistent cough, right hip pain, weight loss• MRI of lumbar spine, T1/T2
hypointense lesion in sacrum• CT chest shows left hilar and lung
mass with innumerable lung nodules in both lungs
EGFR mutation exon 20
PAST MEDICAL HISTORY
Oct 2017 - Biopsy of sacral lesion c/w metastatic non-small cell lung adenocarcinoma
Oct 2017 - Brain MRI shows 5mm frontal and parietal mass
Nov 2017 - Radiotherapy to brain and sacral lesions
Subretinal fluid under fovea
Normal Right eye exam and OCT
Abnormal Left Eye
Subretinal fluid under fovea
Lumpy choroidal infiltration
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T12, R2 B scan
ASSESSMENT
Primary non-small cell lung adenocarcinoma, stage IV, with bone, brain and symptomatic choroidal metastases
Options• External beam radiation• Systemic chemotherapy (non target mutation)• Photodynamic therapy
VERTEPORFIN PHOTODYNAMIC THERAPY3 months later: 20/20
Presentation: 20/50
CHOROIDAL METASTASIS - RADIOTHERAPY
External beam radiation• 20-40 Gy in fractions• 66-84% improved/stabilized
Stereotactic radiosurgery Proton Beam radiation Plaque Brachytherapy
Mathis et al. PRER 2019
ANOTHER CASE
44 yo Asian woman with ductal breast carcinoma• s/p radiation and chemotherapy 1 year ago• Stable regional metastatic disease
2 month history of blurry vision in the right eye• Associated headaches
No prior ocular history or surgery
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ON EXAMINATION
Vision 20/400 right eye 13 x10mm amelanotic
choroidal mass Extensive retinal
detachment Normal left eye
Fluorescein angiographyUltrasonography
BIOPSY OF CHOROIDAL TUMOR
Metastatic breast carcinoma
Concurrent CNS metastasis
Treated with 30 GyEBRT in 15 fractions• Brain and orbit
EXCELLENT RESOLUTION OF LESION AND FLUID
Pre treatmentVision 20/400
3 monthsPost treatment
Vision 20/25
ERBT: COMPLICATIONS
Anterior segment• Skin excoriation, lash loss• Keratopathy• Cataract• Secondary glaucoma
Posterior segment• Retinopathy• Optic neuropathy• Neovascularization
Plaque vs. ERBT• Technique• Timing• complications
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TARGETED THERAPY
ANOTHER CASE…
45 yo white male with acute vision loss in the right eye
No prior ocular history PMH: healthy, non smoker Family history: no malignancy
Indocyanine green angiography Fluorescein angiography
10 x 9 x 3.8mm
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BIOPSY CONFIRMED
Adenocarcinoma of lung• S-100 negative• CK7 and TTF-1 reactive• EGFR mutation positive (SURPRISE!)
Erlotinib therapy initiated 3 weeks later…
3 WEEKS AFTER TREATMENT
What treatment??Erlotinib
EGFR MUTATION POSITIVE LUNG CA
5% of adenoCA cases harbor EGFR mutations Erlotinib TKI approved in May 2013
Outcomes (erlotinib vs. platinum based chemo)• PFS: 10 vs 5 months• Overall survival: 23 vs 20 months• Objective response: 65% vs. 16%
3 cases in literature using TKI for choroidal met
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A DC
B E
ALK-1 genotyp
e
PALLIATIVE CARE: WHEN TO TREAT AND WHY?
Systemic StatusTumor Status
• # of tumors• Location• Laterality
Patient Preference
Observe• Poor status• New therapy
Bilateral disease• Systemic therapy• EBRT
Unifocal, vision involved• PDT, ERBT, plaque, laser
Blind/painful eye• enucleate
OCULAR TOXICITY FROM CANCER THERAPIES
>50 approved anti-cancer therapies since 2008• 34 were antibodies or kinase inhibitors
Often overlooked or underreported side effects• 7% with permanent vision loss
Fu et al. Oncotarget 2017; Kundler et al. Graefe’s Archives Ophthalmol, 2019
ANOTHER CASE
54 yo Vietnamese man with metastatic malignant melanoma
s/p ipilimumab therapy without response Started on interferon infusion therapy
• Moderate initial response Noted vision alterations in both eyes
BILATERAL COTTON WOOL SPOTS
Left eye fundusRight eye fundus
During interferon
3 monthsAfter stopping
interferon
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INTERFERON RETINOPATHY
Recombinant protein used in lymphoma, melanoma, and leukemia therapy
Ischemic retinopathy• Cotton wool spots, hemorrhage in 16-84%• Leukocyte dysfunction and endothelial damage
Drug cessation may reverse
OCULAR TOXICITIES FROM TARGETED AGENTS
Of 46 targeted agents, 20 with FDA label of ocular toxicity• 40% of small molecules• 25% of monoclonal antibodies
Most common FDA label notes• Conjunctivitis, iritis, eye irritation, blurry vision, dry eyes,
Fu et al. Oncotarget 2017
OCULAR SAE TARGETED AGENTS
Most common : conjunctivitis (20%), blurred vision (21%)
Imatinib: 3% of patients with Grade 3+ periorbital edema• Imatinib (70%) and crizotinib (62%) experience any toxicity
Acute vision threatening toxicities• Vascular occlusions, corneal ulceration, retinal findings• 5 drugs: erlotinib, gefitinib, trametinib, vemurafenib, ipilimumab
Branch Vein Occlusion on MEK inhibitor therapy
Microcystic corneal edema on
EGFR inhibitor therapy
Fu et al. Oncotarget 2017
EGFR INHIBITION PRODUCES TRICHOMEGALY IMMUNE CHECKPOINT INHIBITOR TOXICITY
Dalvin et al. Retina 2019
Dry Eye 1-24% Uveitis 1% Myesthenia 1%
Managed with steroids Artificial tears Rarely discontinue
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CHECKPOINT INHIBITOR OCULAR SIDE EFFECTS
Dalvin et al. Retina 2019
MEK ASSOCIATED RETINOPATHY
Subretinal fluid with binimetinibtherapy• 90% during phase 1b/2 studies• 78% after first dose
Bilateral, multifocal and visually symptomatic: 10%
Improved with dose reduction/withdrawl
Weber et al. JAMA Ophthalmology 2016; Mendez-Martinez et al. Retina 2018
Macular edema and serous retinal detachment on
MEK inhibitor therapy
Central serous retinopathy on Small molecule ERK inhibitor therapy
Fu et al. Oncotarget 2017
TARGETED AGENTS: Recommend pre-treatment ophthalmic examinations
• Interferon therapy• EGFR inhibitors• MEK inhibitors (trametinib, selemitinib)• Tyrosine kinase inhibitors (irbruntinib)• Anti –CTLA4 antibodies (ipilimumab)• BRAF inhibitors (vemurafenib)
Most visual complaints in cancer patients are minor
Toxicities can be supported but may require discontinuation
STAGE IV DISEASE WITH OCULAR INVOLVEMENT
This is PALLIATIVE care
Little impact on the primary tumor
Major impact on vision and quality of life
STANFORD OCULAR ONCOLOGY SERVICE
Prithvi Mruthyunjaya, MD, MHS Director
Andrea Kossler, MD Director, Orbital Oncology
Ben Erickson, MDAlbert Wu, MD
Thank you!
OrbitalEyelid
Tumors
Ocular surface Tumors
Intraocular Tumors
Melanoma
Systemic cancers and
the eye
Pediatric Tumors
Retinoblastoma
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Figure 1
A B
Figure 2
A B
OD
OS
OD
OS
OD
OS
METASTATIC IRIS LESIONS
Rare, but important to recognize 5-10% of uveal metastases In 1/3 cases, NO known primary In ½ cases, first sign of metastasis
Very poor prognostic sign
Am . J . O p h t h a l m o l Apr i l 1 9 9 5
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IRIS METASTASES: CLINICAL FEATURES
Unilateral Solitary Epibulbar
injection Secondary
glaucoma
Hyphema Pseudo-hypopion Associated
choroidal metastases
PRIMARY TUMOR LOCATION
Breast• Previously known
history Lung
• Previously unknownhistory
• Biopsy proven Carcinoid tumors Other sites (rare)
ULTRASOUND
High internal reflectivity Less vascularity
A B Metastatic neuroendocrine tumor
Yiu, Cummings, Mruthyunjaya. JAMA Ophthalmology 2015
SOMETIMES YOUR FIRST TREATMENT MAY NOT BE THEBEST… 60 yo gentleman referred for ocular
melanoma evaluation
Otherwise healthy
Choroidal biopsy + for renal cell carcinoma
AFTER EBRTTUMOR GROWTH NOTED
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SUTENT
RAF KINASE INHIBITOR
PARANEOPLASTIC SYNDROME:THE STORY BEGINS… 56 yo wm presents to fantastic local retinal
specialist with right iridociliary mass• Asymptomatic• Incidental finding on CT/MRI
Confirmed findings, initiated metastatic screening
ON PRESENTATION…
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INCIDENTAL MRI FINDING? Admitted 1 month earlier with psychotic
episode Prior pulmonary embolism Chronic pericardial effusion: spiral CT-angio
• Increasing effusion• Stable 1.2mm paratracheal nodes• Patchy lung opacity, atelectasis vs. consolidation
No evidence of liver or CNS disease
Ill appearing male, no systemic malignancy
Melanocyticiridociliary mass
Ciliary body enlargment for >10 clock hours
Differential:• Ring melanoma• Diffuse
infiltrating melanoma
• Metastatic disease
DIFFUSE MELANOMA VS. MELANOCYTIC HYPERPLASIA AT THE SAME TIME..
Post operative desaturation
Atypical chest X-Ray
RIGHT LUNG BIOPSY: NON-SMALL CELL CARCINOMA
Low power tumor growing in nests and along alveolae
High power shows large highly atypical epithelioid cells in nests
HISTOPATHOLOGY FINDINGS
Spindle cells, rarely epithlioid Benign melanocytic hyperplasia Rare mitoses
Pan uveal involvement Widely misreported as diffuse melanoma
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Intraalveolar nests of tumor Focal suggestion of gland formationCytokeratin-7(confirms carcinoma, typically + in lung adenocarcinomas)
TTF-1 (70% adenocarcinomas of lung + for TTF1)
NOT A PRIMARY MELANOMA
HMB45 negative S100 negative
PERICARDIAL BIOPSY: NEGATIVE FOR TUMOR
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PARANEOPLASTIC DISEASE
Cause of significant vision loss
Often may unmask underlying malignancy
Delayed diagnosis• Overlap with numerous retinal conditions
Heckenlively et al. Semin. Immunopathol. (2008)Ferreyra et al. Arch Ophthalmol. (2009)
AUTOIMMUNE RETINOPATHY
Symptoms: photopsias, visual field change
Signs: arteriolar changes, disc pallor, vitritis, ERG loss, scotoma, BDUMP h
CAR MAR npAIR
Autoimmune Retinopathy
Cancer:Small cell lungNon SC lung
BreastCervical
EndometrialProstate
Colonhematologic
Melanoma:CutaneousChoroidal
Ciliary
Non-paraneoplastic:ocular trauma
RPAZOORMEWDS
Birdshot retinopathyidiopathic
Adamus et al. BMC Ophthalmology. (2004)
Heckenlively et al. Semin. Immunopathol. (2008)Ferreyra et al. Arch Ophthalmol. (2009)
Paraneoplastic reaction to retinal S antigen
M ANAGEMENT OF MELANOMA- ASSOCIATED R ETINOPATHY
Handler, Mruthyunjaya, Nelson. J Am Acad Derm. 2011
DIFFUSE UVEAL MELANOCYTIC PROLIFERATION
Paraneoplastic syndrome 60 year old patient (male=female) Early: subtle to few ocular signs Late: vision loss, serous RD, cataract (75%) Death in <1 year
BDUMP: 41 REPORTED CASES
Females MalesGU malignancies Unknown
(pancreas) Lung
All tumors with known paraneoplastic associations ---CAR, hypercalcemia, Cushing’s syndrome
Presentation to death: 1 to 51 months (mean 15 m)
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71-YEAR-OLD MAN WITH BLURRY VISION IN BOTH EYES
4 months vision loss in both eyes, vitritis OU
Uveitis workup was sent. On chest X-ray, he was found to have incidental right upper lobe lung mass.
Slit-lamp exam was notable for 1-2+ AC cells OU and 1+ vitreous haze and inferior vitreous condensations OUWalter, …Mruthyunjaya, et al. JAMA
Ophthalmology 2017
Prithvi Mruthyunjaya, MDAssociate Professor of Ophthalmology and Radiation Oncology
20/150 PH 20/70-
20/200 PH 20/70-
Walter, …Mruthyunjaya, et al. JAMA Ophthalmology 2017
OD OS
06/20/16
05/17/16
OD: 20/160-OS: 20/100-
05/03/16 OD: 20/100-
OS: 20/100-
05/31/16
OD: 20/160-OS: 20/100-
07/21/16
OD: 20/70- PH 20/60-OS: 20/40 PH NI
OD: 20/160-OS: 20/64
plasmaphoresisx6
plasmaphoresisx3
Presentation
OD: 20/100-OS: 20/100-
5/2/2017
OD: 20/25OS:20/30
Walter, …Mruthyunjaya, et al. JAMA Ophthalmology 2017
After plasmaphoresis
