Ultra-High Resolution Optical Ultra-High Resolution Optical Coherence Tomography in the Coherence Tomography in the

Diagnosis of Conjunctival/Corneal Diagnosis of Conjunctival/Corneal Intraepithelial Neoplasia and PterygiaIntraepithelial Neoplasia and Pterygia

Jeremy Z. Kieval, MD; Rodrigo A. Hoffman, MD; Sander R. Jeremy Z. Kieval, MD; Rodrigo A. Hoffman, MD; Sander R. Dubovy, MD; Mohamed A. Shousha, MD, PhD; Jianhua Dubovy, MD; Mohamed A. Shousha, MD, PhD; Jianhua

Wang, MD, PhD; Carol L. Karp, MDWang, MD, PhD; Carol L. Karp, MD

Bascom Palmer Eye Institute, University of Miami, Miami, Bascom Palmer Eye Institute, University of Miami, Miami, FloridaFlorida

The authors have no financial interest in the The authors have no financial interest in the subject matter of this postersubject matter of this poster

AbstractAbstract

• Purpose: Purpose: To assess the use of ultra-high resolution optical coherence tomography (UHR-OCT) in To assess the use of ultra-high resolution optical coherence tomography (UHR-OCT) in distinguishing conjunctiva/corneal intraepithelial neoplasia (CIN) and pterygia, and compare this with distinguishing conjunctiva/corneal intraepithelial neoplasia (CIN) and pterygia, and compare this with histopathologic specimens.histopathologic specimens.

•   • Methods: Methods: 34 eyes with conjunctival/corneal lesions suspicious for CIN or pterygia were imaged with a 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 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 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 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. was measured and differences were examined using a Student’s t-test.

•   • Results: Results: UHR-OCT images of CIN demonstrated striking similarities to histopathologic specimens. Both UHR-OCT images of CIN demonstrated striking similarities to histopathologic specimens. Both

optical and pathological specimens showed a thickened, disorganized layer of epithelium. Likewise, 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 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 showing a normal epithelium, with underlying thickening and hyperreflectivity of the subepithelial mucosal layers. Differences in epithelial thickness between CIN and pterygia were statistically 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 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).pterygium patients (p<0.001).

•   • Conclusions: Conclusions: UHR-OCT may be a promising diagnostic tool for a non-invasive evaluation of ocular UHR-OCT may be a promising diagnostic tool for a non-invasive evaluation of ocular

surface lesions, including CIN and pterygia.surface lesions, including CIN and pterygia.

IntroductionIntroduction

• The term conjunctival intraepithelial neoplasia (CIN) was first coined in 1978 by Pizzarello and The term conjunctival intraepithelial neoplasia (CIN) was first coined in 1978 by Pizzarello and Jacobiac.Jacobiac.11 CIN can involve the conjunctiva, the cornea, or both. This spectrum of disease is often 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 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 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. 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 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. sometimes be difficult to distinguish between other ocular surface lesions.

• The “gold-standard” for diagnosis of OSSN is histopathological specimen by incisional or excisional 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.biopsy. Clinical diagnosis can also be confirmed by brush cytology and impression cytology. 2-6 2-6

• Anterior segment optical coherence tomography (AS-OCT) has the potential to provide a non-invasive, 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 optical biopsy of tissue, where morphologic and even histologic characteristics can be examined in in vivovivo. The recent introduction of AS-OCT has enabled assessment of the conjunctiva and cornea with . The recent introduction of AS-OCT has enabled assessment of the conjunctiva and cornea with high axial resolution of tissue planes.high axial resolution of tissue planes.77 Time-domain technology achieves an axial resolution of Time-domain technology achieves an axial resolution of approximately 18 µm. However, using Fourier (spectral) domain signal analysis, the 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 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 resolution units have allowed axial resolution of 2-3 µm, and have been shown to enable morphologic visualization of both corneal and retinal architecture.visualization of both corneal and retinal architecture.88

• The aim of the present study was to assess the use of an ultra-high resolution optical coherence 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 tomography (UHR-OCT) as an adjuvant tool in diagnosing CIN and pterygia when compared with histopathologic tissue biopsy.histopathologic tissue biopsy.

MethodsMethods• This study was approved by the University of Miami Institutional Review Board (IRB) committee, and was 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 conducted in accordance with the principles of the Declaration of Helsinki. Written, informed consent was obtained from all study participants. obtained from all study participants.

PatientsPatients

• A retrospective review of 34 eyes of 33 patients seen at one institution (Bascom Palmer Eye Institute) 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, 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 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 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.  reviewed for data collection, and the findings were correlated with the pre-operative UHR-OCT images.  

Spectral domain optical coherence tomographySpectral domain optical coherence tomography

• A custom built, high speed and ultra-high resolution spectral domain optical coherence tomography was 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 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 (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 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).in the air and ~3 µm in water or tissue (the refractive index is ~1.39).

Statistical Analysis:Statistical Analysis:

• SPSS software version 17.0 (SPSS, Chicago, IL, USA) was used for statistical analysis. Means of age 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 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 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 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 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.thickness for both groups of subjects are presented to evaluate this measurement as a diagnostic tool.

ResultsResults• Seventeen eyes had conjunctival and/or corneal lesions that disclosed a ocular surface Seventeen eyes had conjunctival and/or corneal lesions that disclosed a ocular surface

neoplasia. neoplasia. • Histopathologic specimens in all patients with CIN demonstrated conjunctival and/or corneal Histopathologic specimens in all patients with CIN demonstrated conjunctival and/or corneal

epithelium with faulty maturational sequencing extending either partial or full thickness. All epithelium with faulty maturational sequencing extending either partial or full thickness. All patients showed acanthotic epithelium often with variable degrees of chronic inflammatory patients showed acanthotic epithelium often with variable degrees of chronic inflammatory cell infiltrates in the substantia propria. An abrupt transition from normal to abnormal cell infiltrates in the substantia propria. An abrupt transition from normal to abnormal epithelium could be demonstrated in obtained pathological specimens. epithelium could be demonstrated in obtained pathological specimens.

• UHR-OCT images of all OSSN lesions were captured and showed a severely thickened, 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 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 affected thickened epithelium was evident. Images were remarkably similar to the histopathological specimens (Figures 1, 2, and 3). histopathological specimens (Figures 1, 2, and 3).

• Seventeen eyes of 16 patients underwent histopathological biopsy of conjunctival and/or Seventeen eyes of 16 patients underwent histopathological biopsy of conjunctival and/or corneal lesions that disclosed a pterygium.corneal lesions that disclosed a pterygium.

• Histopathologic specimens in all patients with pterygia demonstrated a normal conjunctival 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 epithelium without acanthosis. Mild to moderate degrees of actinic change were seen in the underlying substantia propria. underlying substantia propria.

• UHR-OCT images of all pterygia were captured and showed a normal thin epithelial UHR-OCT images of all pterygia were captured and showed a normal thin epithelial architecture, and reflectivity. The underlying subepithelial tissue showed hyper-reflectivity. architecture, and reflectivity. The underlying subepithelial tissue showed hyper-reflectivity. These findings were also very similar to the corresponding histopathologic specimens, as These findings were also very similar to the corresponding histopathologic specimens, as demonstrated in figures 4, 5, and 6.demonstrated in figures 4, 5, and 6.

ResultsResults• Statistical analysis between the two groups is seen in Table 1. Statistical analysis between the two groups is seen in Table 1.

• A statistically significant difference in age between groups was seen with a mean 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 of 70.5 years of age (sd=14) in CIN patients, and 41 years of age (sd=16) in pterygia patients (p<0.001). pterygia patients (p<0.001).

• The difference in epithelial thickness between CIN patients and pterygia patients The difference in epithelial thickness between CIN patients and pterygia patients was statistically significant.  The mean epithelial thickness was 355was statistically significant.  The mean epithelial thickness was 355m (sd=170) in m (sd=170) in CIN patients and 100CIN patients and 100m (sd=22) in pterygium patients (p<0.001, t-test).  m (sd=22) in pterygium patients (p<0.001, t-test). 

• Epithelial thickness in non-tumor areas was also measured in each patient, and Epithelial thickness in non-tumor areas was also measured in each patient, and there was no significant difference between the mean of 93there was no significant difference between the mean of 93m (sd=48) in CIN m (sd=48) in CIN patients, and a mean of 73patients, and a mean of 73m (sd=12) in pterygium patients (p=0.11). m (sd=12) in pterygium patients (p=0.11).

• Receiver operating characteristic (ROC) curves show that there is hardly any 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 overlap between the two groups. The area under the ROC curve is 94%.  The CIN range of epithelial thickness was 68 to 740range of epithelial thickness was 68 to 740m and for pterygia, the range was 69 m and for pterygia, the range was 69 to 136to 136m. m.

• Using 150Using 150m as a cutoff, UHR-OCT has a sensitivity of 94% and specificity of m as a cutoff, UHR-OCT has a sensitivity of 94% and specificity of 100%.  100%.  

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Table 1Table 1

PatientCharacteristic

CINN=17

PterygiumN=17

P-value TotalN=34

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

ConclusionsConclusions• Conjunctival/corneal intraepithelial neoplasia is the most common non-pigmented ocular surface neoplasm.Conjunctival/corneal intraepithelial neoplasia is the most common non-pigmented ocular surface neoplasm. 9,109,10 Surgical Surgical

treatment consists of wide local excision with adjunctive cryotherapy to the surgical margins in a double-freeze-thaw 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 technique. Incomplete excision is common due to diffuse lateral growth, and is associated with a higher incidence of recurrence after surgery.recurrence after surgery.1111 Despite clear surgical margins, recurrence of neoplasia can range from 5% to 33%. Despite clear surgical margins, recurrence of neoplasia can range from 5% to 33%. 11,1211,12

• Recent advances in topical chemotherapeutic agents have become a valuable alternative in the non-invasive 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 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)neoplasia. The principal agents that are used include mitomycin-C (MMC)12-1712-17, 5-fluorouracil (5-FU), 5-fluorouracil (5-FU)18-2018-20, and interferon , and interferon alpha 2β (INFα 2β).alpha 2β (INFα 2β).21-2321-23

• With the advantages of medical therapy for CIN, it would be certainly be ideal in such situations to have a method of 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.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 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 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 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 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 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.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 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 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 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. disease to facilitate complete excision.

• In conclusion, UHR-OCT appears to be a promising technology for a non-invasive diagnosis and surveillance of patients 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 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 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 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 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. to determine the sensitivity and specificity of UHR-OCT in identifying ocular pathology.

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