Transcript The Use of Ultra-High Resolution Optical Coherence

Ultra-High Resolution Optical
Coherence Tomography in the
Diagnosis of Conjunctival/Corneal
Intraepithelial Neoplasia and Pterygia
Jeremy Z. Kieval, MD; Rodrigo A. Hoffman, MD; Sander R.
Dubovy, MD; Mohamed A. Shousha, MD, PhD; Jianhua
Wang, MD, PhD; Carol L. Karp, MD
Bascom Palmer Eye Institute, University of Miami, Miami,
Florida
The authors have no financial interest in the
subject matter of this poster
Abstract
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Purpose: To assess the use of ultra-high resolution optical coherence tomography (UHROCT) in distinguishing conjunctiva/corneal intraepithelial neoplasia (CIN) and pterygia, and
compare this with histopathologic specimens.
Methods: 34 eyes with conjunctival/corneal lesions suspicious for CIN or pterygia were
imaged with a custom built UHR-OCT. Each patient underwent excisional or incisional biopsy
with histopathological diagnosis of the lesion. UHR-OCT images were compared with
histopathologic specimens to determine the correlation between histology and UHR-OCT
images. Epithelial thickness of all UHR-OCT images was measured and differences were
examined using a Student’s t-test.
Results: UHR-OCT images of CIN demonstrated striking similarities to histopathologic
specimens. Both optical and pathological specimens showed a thickened, disorganized layer
of epithelium. Likewise, UHR-OCT images of patients with pterygia were well correlated with
histopathologic specimens showing a normal epithelium, with underlying thickening and
hyperreflectivity of the subepithelial mucosal layers. Differences in epithelial thickness
between CIN and pterygia were statistically significant with a mean epithelial thickness of
355 μm (sd=170) in CIN patients and 100 μm (sd=22) in pterygium patients (p<0.001).
Conclusions: UHR-OCT may be a promising diagnostic tool for a non-invasive evaluation of
ocular surface lesions, including CIN and pterygia.
Introduction
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The term conjunctival intraepithelial neoplasia (CIN) was first coined in 1978 by Pizzarello and
Jacobiac.1 CIN can involve the conjunctiva, the cornea, or both. This spectrum of disease is often
referred to as ocular surface squamous neoplasia (OSSN). The diagnosis can be made clinically by
identification of the characteristic appearance of an elevated, gelatinous, papilliform, or leukoplakic
lesion, often accompanied by a feeder vessel and demonstrating positive Rose-Bengal staining.
However, these lesions can sometimes present in the absence of such “textbook” findings, and can
sometimes be difficult to distinguish between other ocular surface lesions.
The “gold-standard” for diagnosis of OSSN is histopathological specimen by incisional or excisional
biopsy. Clinical diagnosis can also be confirmed by brush cytology and impression cytology.2-6
Anterior segment optical coherence tomography (AS-OCT) has the potential to provide a non-invasive,
optical biopsy of tissue, where morphologic and even histologic characteristics can be examined in vivo.
The recent introduction of AS-OCT has enabled assessment of the conjunctiva and cornea with high
axial resolution of tissue planes.7 Time-domain technology achieves an axial resolution of
approximately 18 µm. However, using Fourier (spectral) domain signal analysis, the axial resolution of
images can be improved to near 8 µm in commercially available units. New custom-built ultra-high
resolution units have allowed axial resolution of 2-3 µm, and have been shown to enable morphologic
visualization of both corneal and retinal architecture.8
The aim of the present study was to assess the use of an ultra-high resolution optical coherence
tomography (UHR-OCT) as an adjuvant tool in diagnosing CIN and pterygia when compared with
histopathologic tissue biopsy.
Methods
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This study was approved by the University of Miami Institutional Review Board (IRB) committee, and was
conducted in accordance with the principles of the Declaration of Helsinki. Written, informed consent was
obtained from all study participants.
Patients
• A retrospective review of 34 eyes of 33 patients seen at one institution (Bascom Palmer Eye Institute) was
performed for the present study. All patients were imaged using a custom built UHR-OCT. Radial, 12mm
images of the appropriate region were acquired at a rate of 32 frames/scan to capture the
conjunctival/corneal lesions. Obtained histopathologic specimens of the remaining 34 eyes were then
reviewed for data collection, and the findings were correlated with the pre-operative UHR-OCT images.
Spectral domain optical coherence tomography
• A custom built, high speed and ultra-high resolution spectral domain optical coherence tomography was
used for this study. This device uses a three-module superluminescent diode (SLD) light source
(Broadlighter, T840-HP, Superlumdiodes Ltd, Moscow Russia) with a center wavelength of 840nm and a
full width at half maximum bandwidth of 100 nm. The calibrated axial resolution of the system was ~4 µm
in the air and ~3 µm in water or tissue (the refractive index is ~1.39).
Statistical Analysis:
• SPSS software version 17.0 (SPSS, Chicago, IL, USA) was used for statistical analysis. Means of age and
measured epithelial thicknesses of the lesions and the adjacent unaffected cornea were compared
between the CIN and the pterygium groups with a two-sided Student t-test. P-values less than 0.05 were
considered statistically significant. Values are presented as means ± standard deviation. Categorical
variables, such as gender, were compared with the chi-square test. Sensitivity and specificity of epithelial
thickness for both groups of subjects are presented to evaluate this measurement as a diagnostic tool.
Results
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Seventeen eyes had conjunctival and/or corneal lesions that disclosed a ocular surface
neoplasia.
Histopathologic specimens in all patients with CIN demonstrated conjunctival and/or corneal
epithelium with faulty maturational sequencing extending either partial or full thickness. All
patients showed acanthotic epithelium often with variable degrees of chronic inflammatory
cell infiltrates in the substantia propria. An abrupt transition from normal to abnormal
epithelium could be demonstrated in obtained pathological specimens.
UHR-OCT images of all OSSN lesions were captured and showed a severely thickened,
hyper-reflective epithelium. In most cases, an abrupt transition between the normal and the
affected thickened epithelium was evident. Images were remarkably similar to the
histopathological specimens (Figures 1, 2, and 3).
Seventeen eyes of 16 patients underwent histopathological biopsy of conjunctival and/or
corneal lesions that disclosed a pterygium.
Histopathologic specimens in all patients with pterygia demonstrated a normal conjunctival
epithelium without acanthosis. Mild to moderate degrees of actinic change were seen in the
underlying substantia propria.
UHR-OCT images of all pterygia were captured and showed a normal thin epithelial
architecture, and reflectivity. The underlying subepithelial tissue showed hyper-reflectivity.
These findings were also very similar to the corresponding histopathologic specimens, as
demonstrated in figures 4, 5, and 6.
Results
• Statistical analysis between the two groups is seen in Table 1.
• A statistically significant difference in age between groups was seen with a mean
of 70.5 years of age (sd=14) in CIN patients, and 41 years of age (sd=16) in
pterygia patients (p<0.001).
• The difference in epithelial thickness between CIN patients and pterygia patients
was statistically significant. The mean epithelial thickness was 355m (sd=170)
in CIN patients and 100m (sd=22) in pterygium patients (p<0.001, t-test).
• Epithelial thickness in non-tumor areas was also measured in each patient, and
there was no significant difference between the mean of 93m (sd=48) in CIN
patients, and a mean of 73m (sd=12) in pterygium patients (p=0.11).
• Receiver operating characteristic (ROC) curves show that there is hardly any
overlap between the two groups. The area under the ROC curve is 94%. The
CIN range of epithelial thickness was 68 to 740m and for pterygia, the range
was 69 to 136m.
• Using 150m as a cutoff, UHR-OCT has a sensitivity of 94% and specificity of
100%.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Table 1
Patient
Characteristic
CIN
N=17
Pterygium
N=17
P-value
Age, mean + SD
70.5 + 14
47.0 + 16
<0.001*
Gender n (%) male
11 (65)
7 (44)
0.4**
18 (55)
Corneal epithelium,
(microns) mean + SD
93 + 48
73 + 12
0.11*
82 + 35
Tumor epithelium
(microns) mean + SD
355 + 170
100 + 22
<0.001*
220 + 173
* Student t-test
** Chi-square test
Total
N=34
Conclusions
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Conjunctival/corneal intraepithelial neoplasia is the most common non-pigmented ocular surface neoplasm.9,10 Surgical
treatment consists of wide local excision with adjunctive cryotherapy to the surgical margins in a double-freeze-thaw
technique. Incomplete excision is common due to diffuse lateral growth, and is associated with a higher incidence of
recurrence after surgery.11 Despite clear surgical margins, recurrence of neoplasia can range from 5% to 33%.11,12
Recent advances in topical chemotherapeutic agents have become a valuable alternative in the non-invasive
management of CIN. They can be used as primary treatment, adjuvant therapy to surgery, or treatment of recurrent
neoplasia. The principal agents that are used include mitomycin-C (MMC)12-17, 5-fluorouracil (5-FU)18-20, and interferon
alpha 2β (INFα 2β).21-23
With the advantages of medical therapy for CIN, it would be certainly be ideal in such situations to have a method of
examining the anterior segment structures with microscopic detail to help guide and tailor such medical treatment.
The results of our study have demonstrated a compelling correlation between images obtained by UHR-OCT and
histopathology in patients with CIN and likewise, in cases of pterygia. With resolution matching that of histologic
specimens, UHR-OCT was able to provide a clear diagnosis of CIN using minimally invasive technology. The applications
of these results are significant. The use of a minimally invasive diagnostic tool can potentially preclude the need for tissue
biopsy causing conjunctival cicitrization and patient discomfort. This is especially important in an era of increasing use of
topical chemotherapeutic agents that obviate the need for surgical excision and cyrotherapy.
In addition to the potential use of UHR-OCT for diagnosis, patient follow-up during the course of medical treatment and
continued surveillance for neoplasia may be possible without the need for repeated biopsies. It may also be helpful in
detecting early recurrent disease, or if a surgical excision is planned, the OCT may be helpful in determining the extent of
disease to facilitate complete excision.
In conclusion, UHR-OCT appears to be a promising technology for a non-invasive diagnosis and surveillance of patients
with CIN. While UHR-OCT is not a substitute for histopathological specimens, it does appear to be a valuable diagnostic
adjuvant in the clinical diagnosis of anterior segment pathology. It may also provide a non-invasive manner to monitor for
recurrence after surgical excision or medical treatment. The high axial resolution provided in cross sectional images
demonstrates an excellent correlation to cellular features in histopathological specimens. Further studies are necessary to
determine the sensitivity and specificity of UHR-OCT in identifying ocular pathology.
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