Over the past few years one of the new imaging technologies we have been exploring is Optical Coherence Tomography an imaging technology that provides high definition imaging in superficial tissue layers using infra-red. The first project, based primarily in Cleveland, Ohio (at the Cleveland Clinic), attempted to develop OCT image criteria that could be used to separate normal from abnormal cervical tissue. On completion of this initial experience with 50 patients we were quite confident we could identify a normal OCT image. In addition OCT was able to visualize the normal microstructure of the various cervix anatomies as well as define characteristics of high grade pre-cancer and cancer.
In our second study, conducted primarily in the Dominican Republic (with a subpopulation from the Cleveland Clinic), 1215 OCT images with matched unmagnified visual inspection using acetic acid (VIA) and colposcope impressions and histology from 212 patients were assessed “remote from the time of the examination” by 3 reviewers. All patients had had VIA, OCT, colposcopy, and biopsies using our validation protocol. Both VIA and colposcopy showed improved specificity when combined with OCT. However, it was clear to us that “time-remote interpretation” of such a dynamic technology was sub-optimal. We then followed with two real time studies in China. In PUSH-OCT I (Shenzhen, China) 299 women were examined with the colposcope with a diagnostic impression made for each quadrant by the operating gynecologist. This was followed by OCT with real-time diagnostic impression and biopsies according to our standard micro-biopsy protocol. The result was a minimum of 4 biopsies per patient with matched OCT images and real-time impressions, plus matched digitized colposcopy images and colposcopy-based diagnoses from each patient. This was our first clinical investigation using the OCT technology “real time”. In addition to improving specificity we have identified two measurable OCT image characteristics that appear to be correlated with the evolving pathologic disease process.
In April of 2008 we completed the fourth of our planned clinical investigations (PUSH-OCT II), this time in the “Buyi-Miao Autonomous District of Guizhou Province China in collaboration with the Peking University Shenzhen Hospital. This study was designed to explore potential application of OCT technology in low-resource settings. Our primary objective was to determine the sensitivity, specificity, positive and negative predictive values for “real time” OCT just using the naked eye (VIA) to guide the OCT device rather than the colposcope. Our secondary objective was to examine the potential for OCT to improve the sensitivity and specificity of VIA and the ease of use of OCT in a real time clinical setting in a rural low resource environment. The subjects came from the villages surrounding the four main towns: Wengan, Sandu, Libo and Duyun, all in Guizhou Province, China. During the Guizhou trial there were several OCT observations noted, such as the “epithelial brightness” first discovered in our Shenzhen studies. However, we found ourselves confused by the multiple variables we had identified and we were not able to adequately incorporate the change in brightness into our real-time “visual” interpretation. We then decided that in order to account for multiple imaging variables in a real time setting, interpretation might be improved with the help of a mathematical algorithm and “computer aided diagnosis.”
Statistical Significance Achieved for Epithelial Brightness as a Defining Characteristic to Evaluate Pre-invasive and Invasive Cervical Cancer
Observations made during our first two China OCT studies led us to analyze the differences in the brightness of the cervical epithelium on Optical Coherence Tomography (OCT) images as a potential distinguishing characteristic of normal, low-grade, high-grade, and cancer histologies. The data from the 300 women who participated in a real-time study of OCT as a diagnostic adjunct to colposcopy and 183 women who participated in a real-time study of OCT as a diagnostic adjunct to VIA were combined to compare the relationship between the brightness of the OCT images to corresponding histology. The abnormal images were expressed in decibels and weighted by the number of images per location. The standard deviation of the average difference in brightness by all patients was also measured. To generate the brightness unit for analysis, the “normal” reading was subtracted from an abnormal reading calculating a change in brightness.For each histological grade mean difference in brightness from normal was calculated. All brightness measures were a log scale. Mean brightness was 0.16, 1.56, 3.36, and 4.71 for squamous metaplasia, CIN II, CIN III, and cancer respectively. Mean brightness differed significantly between each histological grade (p-values 0.000) for the comparisons of CIN II to CIN III, CIN II to cancer, and squamous metaplasia to cancer. For the comparison of mean brightness for CIN III to cancer p=.008. We conclude that epithelial brightness is an important component to include in the development of mathematical algorithms to use for the diagnostic interpretation of OCT generated images of the uterine cervix.
We have since retuned to China (2013) and completed PUSH-OCT III. In this trial we attempted to use OCT diagnosis based on an integrated diagnostic algorithm developed by using the data from PUSH-OCT-II. Data is currently being evaluated.
REFERENCES
1. Int J Gynecol Cancer. 2006 Sep-Oct;16(5):1815-22. doi:
10.1111/j.1525-1438.2006.00665.x.
Optical coherence tomography as a diagnostic aid to visual inspection and colposcopy for preinvasive and invasive cancer of the uterine cervix.
Escobar PF(1), Rojas-Espaillat L, Tisci S, Enerson C, Brainard J, Smith J,
Tresser NJ, Feldchtein FI, Rojas LB, Belinson JL.
Author information:
(1)Department of Gynecology and Obstetrics, Section of Gynecologic Oncology, The
Cleveland Clinic Foundation, Cleveland, Ohio 44118, USA.
The purpose of this study was to determine the sensitivity and specificity of
optical coherence tomography (OCT) under two well-defined clinical settings.
First, as an aid to cervical cancer screening, using visual inspection with
acetic acid (VIA) in low-resource settings, and the second, as an adjunct to the
traditional management of abnormal cervical cytology with colposcopy and biopsy.
Patients referred for colposcopy with > or = atypical squamous cells of
undetermined significance were accrued for the study. Each subject underwent VIA
and colposcopy. OCT was performed in all VIA- and colposcopy-positive areas and
at the squamocolumnar junction in all four quadrants. The sensitivity of VIA for
> or = cervical intraepithelial neoplasia 2 was 76% (95% CI 58-88). When OCT was
applied to VIA as a secondary screen, the specificity improved from 34% (95% CI
27-41) to 61% (95% CI 60-74). With liberal diagnostic criteria for the majority
of the colposcopy examinations, OCT showed an even greater relative improvement
in specificity. OCT proved to be a fair diagnostic modality (receiver operating
characteristic curve 0.73) adjunctive to VIA and colposcopy. On the basis of the
above findings, we believe that this technology could potentially show greatest
utility in the management of cervical dysplasia in low-resource settings where a
single episode of care is most desirable.
DOI: 10.1111/j.1525-1438.2006.00665.x
PMID: 17009977 [Indexed for MEDLINE]
2. Int J Gynecol Cancer. 2010 Feb;20(2):283-7. doi: 10.1111/IGC.0b013e3181cd1810.
Diagnostic efficacy of real-time optical coherence tomography in the management of preinvasive and invasive neoplasia of the uterine cervix.
Liu Z(1), Belinson SE, Li J, Yang B, Wulan N, Tresser NJ, Wang C, Mohr M, Zhang
L, Zhou Y, Weng L, Wu R, Belinson JL.
Author information:
(1)Department of Obstetrics and Gynecology, Peking University Shenzhen Hospital,
Shenzhen, China.
OBJECTIVE: Determine the sensitivity and specificity of optical coherence
tomography (OCT) as an adjunct to colposcopy in the detection of cervical
intraepithelial neoplasia (CIN) grade 2 or higher in a real-time clinical
evaluation.
BACKGROUND: Optical coherence tomography (OCT) uses infrared light similar to
ultrasound pulse-echo imaging. Image resolution is optimal in the 1-to-3-mm
range. This study is the third in our series of OCT investigations and our first
real-time clinical trial. The study was conducted at the Peking University
Shenzhen Hospital, Shenzhen, China.
METHODS: Nonpregnant women 18 years or older with abnormal cervical cytologic
findings or a positive high-risk human papillomavirus test result were
recruited. Women were assessed; and diagnoses, recorded by cervical quadrant
first with colposcopy, followed by colposcopic directed OCT. A biopsy of the
abnormal areas was performed. In normal quadrants, biopsy specimens were
obtained at the 2-, 4-, 8-, and 10-o’clock positions at the squamocolumnar
junction depending on the quadrant. An endocervical curettage was also done.
Individual OCT diagnoses were paired with colposcopic impressions and biopsy
specimens to assess its role as a paired secondary screen. Data were analyzed
using generalized estimating equations to control for correlation within a
woman.
RESULTS: One thousand two hundred thirty-seven paired diagnoses from 299 women
were analyzed. Median age was 36 years. Ninety-six women (8%) had a diagnosis of
CIN 2 or higher. Evaluation by quadrant showed that the sensitivity for CIN 2 or
higher decreased by adding OCT to colposcopy, but the specificity increased from
83% to 93%.
CONCLUSIONS: We continue to try to improve sensitivity by improving the
near-infrared light source, decreasing the scan time to 8 frames per second, and
using a larger diameter (5 mm) fiberoptic probe with a newly designed
application specific probe sheath.
DOI: 10.1111/IGC.0b013e3181cd1810
PMID: 20134271 [Indexed for MEDLINE]
3. Int J Gynecol Cancer. 2010 Apr;20(3):422-7. doi: 10.1111/IGC.0b013e3181d09fbb.
Study of the diagnostic efficacy of real-time optical coherence tomography as an adjunct to unaided visual inspection with acetic acid for the diagnosis of preinvasive and invasive neoplasia of the uterine cervix.
Wulan N(1), Rasool N, Belinson SE, Wang C, Rong X, Zhang W, Zhu Y, Yang B,
Tresser NJ, Mohr M, Wu R, Belinson JL.
Author information:
(1)Department of Obstetrics and Gynecology, Peking University, Shenzhen
Hospital, 1120 Lianhua Rd, Futian Shenzhen, China. wlnaa@hotmail.com
OBJECTIVES: To determine the sensitivity and specificity of optical coherence
tomography (OCT) as an adjunct to unaided visual inspection using acetic acid
(VIA) in the detection of cervical intraepithelial neoplasia 2 (CIN 2) in a
real-time clinical evaluation.
BACKGROUND: This clinical study was a prospective cross-sectional comparative
trial that screened 1000 patients (aged 30-50 years) in a low-resource setting.
Women with abnormal cervical cytology or positive human papillomavirus (HPV)
tests were referred for further evaluation including VIA, OCT imaging,
colposcopy, and cervical biopsies.
METHODS: The VIA diagnoses were coded by quadrant. The OCT was then performed in
all VIA-positive areas and at the squamocolumnar junction in all 4 quadrants.
All patients were colposcoped; assessed by quadrant with biopsies at 2, 4, 8,
and 10 o’clock; all abnormal areas were biopsied; and endocervical curettage was
performed. Data were analyzed using generalized estimating equations and
logistic regression.
RESULTS: Of the 1000 patients, 175 (17.5%) were HPV positive, 93 (9.3%) had
abnormal cervical cytology greater than or equal to atypical squamous cells of
undetermined significance, and 211 (21.1%) were either HPV positive or had
abnormal cytology. The VIA, OCT, colposcopy, and biopsies were completed on 183
(86.7%) of 211 women. For VIA alone, the sensitivity and specificity in
detecting lesions greater than or equal to CIN 2 was 43% and 96%. With the
addition of OCT, the sensitivity increases to 62% with a specificity of 80%.
CONCLUSIONS: With the addition of OCT, the sensitivity of VIA increased in all
analyses for the detection of greater than or equal to CIN II, with a loss in
specificity. We hope that the potential of this technology will be realized when
a computer algorithm is generated to aid in image interpretation.
DOI: 10.1111/IGC.0b013e3181d09fbb
PMID: 20375808 [Indexed for MEDLINE]
4. Med Phys. 2011 Jan;38(1):107-13. doi: 10.1118/1.3523098.
Diagnostic efficacy of computer extracted image features in optical coherence tomography of the precancerous cervix.
Kang W(1), Qi X, Tresser NJ, Kareta M, Belinson JL, Rollins AM.
Author information:
(1)Department of Biomedical Engineering, Case Western Reserve University, 319
Wickenden Building, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA.
wxk29@case.edu
PURPOSE: To determine the diagnostic efficacy of optical coherence tomography
(OCT) to identify cervical intraepithelial neoplasia (CIN) grade 2 or higher by
computer-aided diagnosis (CADx).
METHODS: OCT has been investigated as a screening/diagnostic tool in the
management of preinvasive and early invasive cancers of the uterine cervix. In
this study, an automated algorithm was developed to extract OCT image features
and identify CIN 2 or higher. First, the cervical epithelium was detected by a
combined watershed and active contour method. Second, four features were
calculated: The thickness of the epithelium and its standard deviation and the
contrast between the epithelium and the stroma and its standard deviation.
Finally, linear discriminant analysis was applied to classify images into two
categories: Normal/inflammation/CIN 1 and CIN 2/CIN 3. The algorithm was applied
to 152 images (74 patients) obtained from an international study.
RESULTS: The numbers of normal/inflammatory/CIN 1/CIN 2/CIN 3 images are 74, 29,
14, 24, and 11, respectively. Tenfold cross-validation predicted the algorithm
achieved a sensitivity of 51% (95% CI: 36%-67%) and a specificity of 92% (95%
CI: 86%-96%) with an empirical two-category prior probability estimated from the
data set. Receiver operating characteristic analysis yielded an area under the
curve of 0.86.
CONCLUSIONS: The diagnostic efficacy of CADx in OCT imaging to differentiate
high-grade CIN from normal/low grade CIN is demonstrated. The high specificity
of OCT with CADx suggests further investigation as an effective secondary
screening tool when combined with a highly sensitive primary screening tool.
DOI: 10.1118/1.3523098
PMCID: PMC3017583
PMID: 21361180 [Indexed for MEDLINE]
5. J Low Genit Tract Dis. 2013 Apr;17(2):160-6. doi: 10.1097/LGT.0b013e31825d7bf0.
Cervical epithelial brightness by optical coherence tomography can determine histological grades of cervical neoplasia.
Belinson SE(1), Ledford K, Rasool N, Rollins A, Wilan N, Wang C, Rong X, Zhang
W, Zhu Y, Tresser N, Wu R, Belinson JL.
Author information:
(1)Preventive Oncology International, Inc., Cleveland Heights, USA.
OBJECTIVE: The study aimed to determine if the difference in cervical epithelium
brightness, as measured by optical coherence tomography (OCT), has potential as
a distinguishing characteristic of normal, low-grade, high-grade (cervical
intraepithelial neoplasia 2+), and cancer histological findings.
MATERIALS AND METHODS: Information from 476 women was available for analysis.
Demographic information was collected through in-person interview. All
participants were human papillomavirus positive and/or had abnormal cytological
finding and underwent colposcopy or unaided visual inspection and examination by
OCT by quadrant. All women had a minimum of 4 OCT-matched cervical biopsies and
endocervical curettage. Two sample t tests were used to measure differences in
OCT image brightness by histological grades.
RESULTS: Mean OCT image brightness differed significantly between each
preinvasive histological grade and invasive cancer (p < .01 for all
comparisons). Brightness as measured by OCT was also able to differentiate
between squamous metaplasia and cervical intraepithelial neoplasia 3/cancer; p
values were .004 and .003, respectively.
CONCLUSIONS: Epithelial brightness is an important component of cervical
epithelium diagnosis by OCT, and we plan to add it to our diagnostic
mathematical algorithm in all future versions of OCT software.
DOI: 10.1097/LGT.0b013e31825d7bf0
PMID: 23343696 [Indexed for MEDLINE]