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Phison Le, MS OD
Resident at VA Boston Healthcare System, Jamaica Plain
Abstract submission for Academy of Optometry Conference 2012
Eye Cancer: Yes or No?
Multi-Modal Imaging of Limbal Lesions
Phison Le, MS OD
Four patients with suspicious limbal lesions are evaluated and diagnosed with utilization of
novel diagnostic imaging technology: confocal microscopy and spectral domain optical
coherence tomography (SD-OCT). Clinical cases are illustrated via slit lamp photography and
images from OCT & confocal microscopy.
 Case History #1
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Patient Demographics
o 51 y.o. white male, retired army general
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Chief Complaint
o Assessment for ocular damage incurred during his tour of duty in the Middle East
from 1996-2007.
Ocular History
o chronic exposure to smog, smoke (burning gas fuels), airborne debris
o chronic dry eye with injection, relief with daily use of artificial tears
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Medications
o None
Pertinent Medical History:
o Patient is a carrier for cystinosis
Pertinent Findings
o Clinical OD:
 1-round, dense, leukoplakic opacity within anterior stroma at 7 o’clock
with iron line, adjacent conjunctival hyperplasia and vasculature (-)
corkscrew in shape
o OS:
 2-round, dense leukoplakic opacities within anterior stroma at 7 o’clock
with iron line, adjacent conjunctival hyperplasia and vasculature (-)
corkscrew in shape
 1 faint anterior stromal irregularity at 4 o’clock with iron line , adjacent
circumferential conjunctival hyperplasia and vasculature (-) cork screw in
shape
o Lesions stained minimally with rose-bengal OU
o OCT shows intact, thin, hyporeflective corneal epithelium with subepithelial lesions.
o Confocal microscopy showed uniform, hyperreflective uni-nucleate corneal
epithelium. However, atypical fibroblasts were visualized at the level of the stoma.
Differential diagnosis
o Primary diagnosis/leading:
Phison Le, MS OD
Resident at VA Boston Healthcare System, Jamaica Plain
Abstract submission for Academy of Optometry Conference 2012
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Atypical pterygia: Lesions did not stain with sodium fluorescein. The
corneal epithelium was of average thickness & only uni-nuclear epithelial
cells were seen on confocal microscopy despite the presence of an abrupt
change in the epithelial interface on OCT. In addition, atypical fibroblasts
were detected at the level of the stroma on confocal microscopy suggestive
of atypical pterygia instead of CIN.
Others
 Conjunctival Intra-epithelial Neoplasia (CIN): The lesion would have to be
localized within the corneal epithelium. In addition, confocal microscopy
would have needed to show multi-nucleate cells or polymorphous cells as
well as stronger nuclear and membrane signals.
 Conjunctival scar: SLO of the conjunctival scar would reveal a dense
hyperreflectance at the level of corneal stroma.
 Case History # 2
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Patient demographics
o 66 y.o. white male
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Chief Complaint
o Long-standing monocular diplopia OS & binocular diplopia secondary to orbital floor
fracture and muscle entrapment OS x 3 years.
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Ocular History
o Corneal scars secondary to foreign body OU
o Enopthalmos OS
o H/o of chronic sun exposure without UV protection
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Medical History: Arthritis, Hyperlipidemia, DM, Type I, Post-traumatic Stress Disorder
Depressive Disorder
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Medications: Amitriptyline, Lidocaine, Omeprazole, Cholecalciferol, Rosuvastatin,
Carboxymethylcellulose, Aspirin
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Pertinent Findings
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Clinical
 OU: White, gelatinous, conjunctival lesion with hairpin vessels located
nasally
 Inferior corneal staining OS>>OD
 Lesions did not stain with NaFL
Phison Le, MS OD
Resident at VA Boston Healthcare System, Jamaica Plain
Abstract submission for Academy of Optometry Conference 2012
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Optical coherence tomography shows intact corneal epithelium with
subepithelial lesions OU. However, there is an abrupt change in the
epithelial interface OS.
Confocal microscopy was not suggestive of epithelial cell dysplasia.
However, atypical fibroblasts were seen in the stroma.
Differential diagnosis
o Primary diagnosis/leading:
 Atypical pinguecula: Lesions did not stain with sodium fluorescein. The
corneal epithelium was of average thickness & only uni-nuclear epithelial
cells were seen on confocal microscopy despite the presence of an abrupt
change in the epithelial interface on OCT. Normal keratocytes were
visualized at the level of the stroma.
o Others
 Conjunctival Intra-epithelial Neoplasia (CIN): The lesion would have to be
localized within the corneal epithelium. In addition, confocal microscopy
would have needed to show multi-nucleate cells or polymorphous cells as
well as stronger nuclear and membrane signals.
 Conjunctival scar: SLO of the conjunctival scar would reveal a dense
hyperreflectance at the level of corneal stroma.
 Case History #3
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Demographics
o 76 year old white male
Chief Complaint:
o Referred to clinic for suspicious nasal lesion status-post cataract extraction OD.
Patient is asymptomatic.
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Ocular History:
o Glaucoma OS
o Corneal edema OD
o N-AION
o Narrow angles, s/p LPI OU
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Medical History: None on record
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Medications: Alphagan, Timolol, Predforte
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Pertinent Findings
o Clinical:
Phison Le, MS OD
Resident at VA Boston Healthcare System, Jamaica Plain
Abstract submission for Academy of Optometry Conference 2012
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There is an area of corneal subepithelial scar (6mm x 4mm) with an adjacent
iron line and a small area of nasal pannus.
The lesion was not mentioned in notes until September 2011
Old records indicate progression: the lesion was previously noted to have
extended only to the pupillary margin. However, it has now extended over the
pupil
Anterior segment photos, confocal microscopy, and optical coherence
tomography were obtained. Results of confocal microscopy and slit lamp
examination were highly suggestive for conjunctival intra-epithelial neoplasia
(CIN) .
The suspected diagnosis and treatment were discussed with the patient. The
patient decided to undergo treatment and was placed on interferon alpha-2b
1MU/ML.
The patient is being monitored through diagnostic imaging for resolution of the
lesion over time.
OS: clear
Differential diagnosis
o Primary diagnosis/leading:
 Conjunctival Intra-epithelial neoplasia (CIN): Despite a low-suspicion for CIN
on OCT. The clinical appearance of the lesion was suspicious for malignancy.
Moreover, confocal microscopy showed dysplastic epithelial cells with
stronger nuclear and membrane signals than epithelial cells outside the
suspicious zone.
o Others
 Atypical pterygium: Lesions did not stain with sodium fluorescein. The
corneal epithelium was of average thickness & only uni-nuclear epithelial
cells were seen on confocal microscopy despite the presence of an abrupt
change in the epithelial interface on OCT. The primary lesion was also
located in the anterior stroma.
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Conjunctival scar: SLO of the conjunctival scar would reveal a dense
hyperreflectance at the level of corneal stroma.
 Case History #4
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Patient demographics
o 68 y.o. white male
Chief Complaint
o The patient noticed a suspicious lesion OS x 10 days and presented to an outside
clinic for evaluation. The patient was then referred to the Boston Veterans Affairs
Healthcare System for a suspected conjunctival intra-epithelial neoplasia (CIN) OS.
Ocular History
Phison Le, MS OD
Resident at VA Boston Healthcare System, Jamaica Plain
Abstract submission for Academy of Optometry Conference 2012
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Laser procedure OS
Cataracts
Pinguecula OU
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Medications: Nifedipine, Glyburide, Hydrochlorothiazide,Insulin , Colchicine, Glucose
Omeperaole, Aspirin 81 mg, Sleeping pill
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Medical History
o Squamous cell skin carcinoma removed from left knee
o Actinic Keratosis removed from scalp
o History of sun exposure, cigarette exposure
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Pertinent Findings
o Clinical
 Small seborrheic keratosis on upper lid margin OS
 Small nasal and temporal pinguecula OD
 Small nasal lesion (4.5 x 2.5 mm) along inferior temporal limbus with a
leukoplakic center (1x1.5mm) OS
 Anterior segment photos, confocal microscopy, and optical coherence
tomography were obtained. Data strongly supported a diagnosis of conjunctival
intra-epithelial neoplasia (CIN).
 The patient was placed on interferon alpha-2b 1MU/ML and will be followed via
diagnostic imaging for resolution of the CIN over time.
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Differential diagnosis
o Primary diagnosis/leading:
 Conjunctival Intra-epithelial neoplasia (CIN): The clinical appearance of the
lesion was suspicious for malignancy. In addition, the lesion was localized
within the corneal epithelium with an abrupt change in the epithelial
interface on OCT. Moreover, confocal microscopy showed dysplastic
epithelial cells with stronger nuclear and membrane signals than epithelial
cells outside the suspicious zone.
o Others
 Atypical pterygium: Lesions did not stain with sodium fluorescein. The
corneal epithelium was of average thickness & only uni-nuclear epithelial
cells were seen on confocal microscopy despite the presence of an abrupt
change in the epithelial interface on OCT. The primary lesion was also
located in the anterior stroma.
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Conjunctival scar: SLO of the conjunctival scar would reveal a dense
hyperreflectance at the level of corneal stroma.
Diagnosis and Discussion
Phison Le, MS OD
Resident at VA Boston Healthcare System, Jamaica Plain
Abstract submission for Academy of Optometry Conference 2012
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Ocular surface squamous neoplasia (OSSN) and limbal lesions such as pterygia result
from mutational changes in limbal epithelial cells.
Morphological and histological changes in epithelium result in either benign, actinic
changes or malignant dysplasia.
Exposure to ultraviolet B radiation and environmental toxins cause morphological
and histological changes at the limbus
Mutations result in hyperplasia of the cells as they migrate into the cornea and
conjunctiva.
Benign lesions such as pterygia migrate into the subepithelial space sparing the
corneal epithelium. Bowman’s membrane remains intact except at the leading edge
of the pterygia where it will be broken down by concentrated matrix
metalloproteinases (MMPs).
Conjunctival intra-epithelial neoplasia (CIN) is mild dysplasia of limbal epithelium.
The lesion invades the corneal epithelium while respecting bowman’s membrane
and the substantia propia of the conjunctiva.
More severe forms include carcinoma in situ and invasive squamous cell carcinoma
(SCC); which metastasize into adjacent corneal and conjunctival layers.
The gold standard for diagnosis is biopsy with histological analysis. However, slit
lamp examination and photos are more often utilized.
Benign limbal lesions do not stain with NaFl nor Rose-Bengal.
Malignant lesions such as CIN appear gelatinous, with an irregular surface and
leukoplakic or gray in appearance.
Histological analysis remains gold standard for diagnosis of limbal lesions.
Hairpin feeder vessels increases suspicion for diagnosis of CIN. These lesions invade
the epithelium and will stain with NaFL/Rose Bengal.
Optical coherence tomography and confocal microscopy have been used to perform
non-invasive analysis of these lesions; with high sensitivity and specificity.
The OCT is able to locate the layer within which the lesion resides
Confocal microscopy identifies irregular cell features that are associated with
dysplasia as it examines sections of the cornea along the z-axis.
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Expound on unique features
o All four patients had suspicious lesions that were difficult to diagnose based on SLE and
photos alone. Confocal microscopy & OCT provided additional information when
histological results were not readily available to determine diagnoses, guide appropriate
treatment, and monitor response to treatment.
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Treatment & Management
o Patients # 1 & 2 (pterygium & pinguecula) are being monitored through diagnostic
imaging for changes over time.
o Patient # 3 &4 were suspected to have CIN. They were both placed on interferon alphab2 and are being closely monitored.
o Treatment for limbal lesions depends on the diagnosis, extent and severity of the lesion.
Phison Le, MS OD
Resident at VA Boston Healthcare System, Jamaica Plain
Abstract submission for Academy of Optometry Conference 2012
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Pterygia & pinguecula are monitored, patients are advised to wear uv-protected lenses,
artificial tears are advised to reduce ocular irritation. If lesion encroaches on the visual
axis and/or if patients are highly symptomatic then surgical excision is performed.
Patients with suspected CIN may undergo an excisional biopsy with concurrent
administration of interferon alpha-b2, mitomycin C, or 5-fluorouracil.
Recurrence rate for pterygia and CIN are high. Therefore, patients with previous CIN
diagnosis should be monitored on an annual basis.
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Refer to research where appropriate
o OCT of normal corneal epithelium
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Dark, thin, and uniform layer. The outline of Bowman’s layer is visible.
Stroma and Descemet’s layer appear dark, without hypereflectivity [Chiou]
o OCT OSSN
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Sharp disparity in reflectivity of normal and diseased epithelium [Chiou]
o OCT Pterygia
 Subepithelial hyperreflectivity with loss of Bowman’s membrane at the
leading edge of lesion [Dushku]
 Differences in measured epithelial thickness between OSSN & pterygia are
346 um (SD, 167) and 101 um (SD 22) [Kieval].
o Confocal microscopy of normal cornea [Niederer, Malandrini]:
 Superficial layers have roundish epithelial cells, demonstrate moderately
reflective nuclei
 Basal epithelial cells have hyporeflective nuclei, but hyperreflective
membranes. Avg. number of cell sides is 5.5+/-0.1 sides .
 Smaller basal cells are found at the limbus and may correlate with epithelial
stem cells. Langerhan cells present as either large cells bearing long
processes or smaller cells lacking dendrites.
 Bowman’s layer is acellular with hyperreflectivity. Subepithelial nerve plexus
can be identified at this layer.
 Stroma will have hyperreflective keratocyte nuclei scattered against a dark
background. Cell density is highest in the anterior stroma.
o Confocal Microscopy in CIN [Malandrini]:
 Corneal epithelium shows larger, irregular bright cells with hyperreflective
larger nuclei. Some cells can be multi-nucleate.
 There will be moderately stronger cell signal strength
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Bibliography, literature review encouraged
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Chiou AG, Kaufman SC, Kaufman HE, Beuerman RW. Clinical corneal confocal
microscopy. Surv Ophthalmol. Sep-Oct 2006;51(5):482-500.
Dushku N, John MK, Schultz GS, Reid TW. Pterygia pathogenesis: corneal invasion by
matrix metalloproteinase expressing altered limbal epithelial basal cells. Arch
Ophthalmol. May 2001;119(5):695-706.
Phison Le, MS OD
Resident at VA Boston Healthcare System, Jamaica Plain
Abstract submission for Academy of Optometry Conference 2012
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Jaworski A, Wolffsohn JS, Napper GA. Detection, aetiology and management of
conjunctival intraepithelial neoplasia. Ophthalmic Physiol Opt. Sep 2000;20(5):371380.
Kiire CA, Dhillon B. The aetiology and associations of conjunctival intraepithelial
neoplasia. Br J Ophthalmol. Jan 2006;90(1):109-113.
Kieval JZ, Karp CL, Abou Shousha M, et al. Ultra-high resolution optical coherence
tomography for differentiation of ocular surface squamous neoplasia and pterygia.
Ophthalmology. Mar 2012;119(3):481-486.
Malandrini A, Martone G, Traversi C, Caporossi A. In vivo confocal microscopy in a
patient with recurrent conjunctival intraepithelial neoplasia. Acta Ophthalmol. Sep
2008;86(6):690-691.
Niederer RL, McGhee CN. Clinical in vivo confocal microscopy of the human cornea
in health and disease. Prog Retin Eye Res. Jan 2010;29(1):30-58.
Shousha MA, Karp CL, Perez VL, et al. Diagnosis and management of conjunctival
and corneal intraepithelial neoplasia using ultra high-resolution optical coherence
tomography. Ophthalmology. Aug 2011;118(8):1531-1537.
Shousha MA, Perez VL, Wang J, et al. Use of ultra-high-resolution optical coherence
tomography to detect in vivo characteristics of Descemet's membrane in Fuchs'
dystrophy. Ophthalmology. Jun 2010;117(6):1220-1227.
Vajzovic LM, Karp CL, Haft P, et al. Ultra high-resolution anterior segment optical
coherence tomography in the evaluation of anterior corneal dystrophies and
degenerations. Ophthalmology. Jul 2011;118(7):1291-1296.
Conclusion
o Clinical pearls, take away points
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Limbal lesions do not always have a textbook clinical appearance
Novel OCT & confocal microscopy act as adjunct diagnostic tests that provide noninvasive morphological and histological analysis of suspicious lesions
OCT and confocal microscopy can be utilized to monitor resolution & recurrence of
limbal lesions such as subclinical CIN