Initial data, capabilities and limitations conclusions, and diagnostic usefulness recommendations derived from application of our endoscopic optical coherence tomography (EOCT) system to the imaging of the mucous membranes of human internal organs are presented herein based on in vivo study of more than 100 patients. These data suggest that EOCT can provide, non-invasively and innocuously, such significant clinical diagnostic information as the following: identification and localization of informative internal biopsy sites; structural characterization of normal and abnormal internal mucosal tissues; guidance in the rendering of surgical and non-surgical treatments; and monitoring of the functional states (both normal and abnormal) of internal orgarns and post-operative recovery processes in the same. This investigation demonstrated that OCT data is more informative for organs with epithelial tissues separated from their underlying stroma by a smooth basal membrane; therefore, this report focuses on the EOCT study of three such internal organs - the larynx, the bladder, and the uterine cervix. Additionally reported herein, for the first time, is the laparascopic OCT examination of the mucosal lining of the abdomen.
© Optical Society of America
Optical coherence tomography , having passed through a period of rapid development as a new method of bioimaging, is now gradually entering the domain of concrete clinical applications. Historically, the first biomedical applications [2–4] of OCT, those that stimulated a more widespread interest, were in ophthalmology. This fact is understandable in that eye tissue is quite transparent to near infrared light, and its weakly scattering structures, including the retina, can be imaged by OCT to the full depth without difficulty. Dermatology  also appeared to be a promising application field for OCT due to the obvious ease of recording skin images. However, it turned out that skin is a much less favorable subject for OCT imaging than previously thought because of strong scattering of the probing light and poor optical contrast between structural components in clinically important areas. Even recent applications of OCT in dentistry [6–8] for imaging hard tooth tissues have encountered less technical difficulties than those in dermatology.
From the very beginning, mucous membranes of internal organs have attracted considerable attention as a potentially interesting target tissue for application of OCT technology. Early on in vitro OCT images [9–11] were recorded of those tissues which, particularly as regarded the opportunity to observe distinctly tumor margins in the mucosa of the GI tract, inspired optimism for the technology. The implementation of the endoscopic OCT has been hampered by the absence of a special optical probe to provide low coherence radiation access to the investigated tissue in vivo. An attempt to construct such a probe has been based on the use of a catheter similar to that employed in the endoscopic ultrasound technique, utilizing the same axial scanning mode . By now, this effort should have resulted in recording EOCT images of GI and respiratory tracts in animals. In one of our previous papers , the implementation of another endoscopic OCT probe is reported that is compatible with standard clinical endoscopic equipment and is introduced to the studied tissue through a biopsy channel. This approach has resulted in the creation of a whole family of joint endoscopic/OCT diagnostic systems and allowed our recording of the first collections of OCT in vivo images of the human mucosa in the GI, respiratory, urinary, and genital tracts.
In the present paper, an initial attempt is made to draw conclusions (based on one year’s effort with more than 100 patients) about the capabilities and limitations of EOCT with regard to human organ internal mucous membrane imaging and to make clinical diagnostic usefulness recommendations regarding the same. It now appears clear EOCT is useful in this regard for at least the following purposes:
- performing biopsies;
- monitoring functional states of human organs (and, thus, the body as a whole);
- guiding surgical and other treatments;
- monitoring post-operative recovery processes.
In medical practice, the choice of location for an excisional biopsy is usually based on visual examination or accumulation of biochemical data over a rather large tissue area, which often results in clinical errors. OCT has the capability to indicate exactly the margin of an area with structural alterations and, therefore, can provide an accurate map for excisional biopsy. It is highly probable that in the future improved OCT images may provide sufficient diagnostic information to serve as a noninvasive optical biopsy technique. This technique may be especially important when excisional biopsy presents hazards to patients or may accelerate, or undesirably alter, a pathological process. Non-invasive optical biopsy might also be useful when an immediate in situ decision-making tool is needed during the course of surgery.
The mucosa of internal organs undergo structural alterations (not necessarily pathologic) which are reflective of the general state of the body or its specific functional processes. Monitoring of these alterations over time (i.e., functional OCT imaging) is one of the interesting applications of EOCT. Later in this report, a specific example of the capability of this application, evaluation of the hormonal activity of the body, will be demonstrated.
The high acqusition rate and precision of OCT imaging make it an excellent technique for providing guidance for surgical and other treatments. For example, surgery of the larynx often requires removal of tissue with millimeter precision. Of particular interest in this regard is the integration of a microsurgical laser with an OCT device in the same equipment, having an optical system in common for aiming both the laser and the probing beams, which would provide permanent, high precision OCT control of surgical treatment.
EOCT can also be used to evaluate the course of a treatment post-operatively, monitoring over time the process of tissue regeneration. This application does not necessarily require fast analysis of the mucosal tissue, but rather is based on the capability of OCT to precisely monitor periodically (e.g., daily, weekly, etc.) the evolving changes in the internal mucosal structure, a capability important to determining the necessity for repeated or supplementary treatment. Of course, when observing the tissue before and after treatment, the applied technique can not guarantee imaging exactly the same region with the pixel-size precision. Therefore, the comparative analysis of images in those cases is qualitative, demonstrating the main features of the tissue recovery.
Clearly, the mucosa of different internal organs is not equally amenable to OCT imaging. Our experience is that OCT imaging is more informative in the case of internal organs covered with stratified squamous epithelium separated from underlying stroma by a smooth basal membrane. Such is the case in the larynx, the uterine cervix, and the esophagus, and due to the different scattering properties of their epithelia and stroma, the position of their basal membrane can be distinctly seen in OCT images. Violation of the integrity of these basal membranes, as detected by our OCT technique, is a sign of pathology. For internal organs covered with a thin transitional or columnar epithelium over a smooth basal membrane (e.g., bladder, endocervix, etc), the position of this membrane is not so easily observable with OCT; however, a horizontal (lateral) internal image architecture is typically evident.
Another important tissue feature that is also easily detected by EOCT is a change in the relationship between the sizes of different tissue layers. As will be demonstrated later in the report, this fact can be used for determining by OCT imaging the functional states of these internal organs (and, by extrapolation, the body as a whole). The loss of normal structural form in the normal mucosa is another diagnostic tissue feature detectable by EOCT. This loss usually occurs at a border between healthy tissue and a tumor and can be defined precisely as to position and extent by OCT.
For mucosa with an uneven basal membrane surface (e.g., stomach, intestines, etc.), a horizontal architecture within the OCT images is not so evident and the simple diagnostic signs mentioned above are not as applicable. In these cases, imaging of the exact form of the basal membrane requires a higher spatial resolution. In one of our previous publications , the vertical architecture of stomach mucosa has been demonstrated in vivo by OCT imaging. Several in vitro OCT images of the GI tract confirming this architecture have been obtained by other groups.
The remainder of this report will focus on our OCT study of three internal organs -the larynx, the bladder, and the uterine cervix. As mentioned previously, these organs have favorable OCT imaging properties, but also are extremely important organs when it comes to early tumor diagnostic techniques and organ-preserving methods of treatment.
In spite of a large total number of examined cases, each group corresponding to a concrete imaged organ and disease consisted of a rather limited number of patients. Therefore, at this stage of the research, we have not pursued the goal to accumulate any comprehensive medical statistics. The main task has been to find out clear tomographic signs of different types of abnormalities as compared to the healthy tissue. In this paper we describe only those OCT signs that have necessarily been present in all patients with a given disease diagnosed earlier by using other generally accepted methods of examination.
This research was accomplished using our endoscopic OCT device described in a previous publication . Images were recorded at the wavelength of 0.83 microns, with a probing light power of 0.5 mW, and a single-frame acquisition time of approximately one second. Though the application of a longer wavelength (e.g. 1.3 micron) would result in deeper imaging, the radiation source used in our study provided us with a sufficient spatial resolution (15 micron) and sharp pictures of clinically important outer region of mucosa, first of all in the neighborhood of the basal membrane whose state is one of the main observable features for OCT.
Most images were obtained using a single B-scan recording cycle; however, in some cases, under appropriate experimental conditions, a 3–5 times averaging procedure was used. Image vertical scales are shown in “media millimeters”, taking into account an “average” group refractive index of n=1.4, which means that all “free space” distances are divided by n.
A new modality, not used in our previous studies [13–15], is introduced in this report - the integration of OCT with laparoscopy. Instead of using a biopsy channel of an endoscope to conduct the insertion of a flexible OCT probe, in this new instrument the probe is inserted through a troacar equipped with a special holder. The aiming of the probing beam is controlled by using the monitor of a standard laparoscopic video system. In the last section of this report, the laparoscopic OCT examination of the mucosal lining of the abdomen is demonstrated for the first time.
2. EOCT of the urinary bladder
EOCT capabilities for imaging of the urinary bladder were studied in nine patients, all girls, ages 5–14 years. The patients suffered from diurnal and nocturnal enuresis.
It is known  that this disease can be caused by genetic problems and nervous system pathology. Nocturnal enuresis can also result from flaccid infection inflammatory processes of the urinary system. Diagnosis of these processes is especially difficult in children because of the frequent asymtomatic course of cystitis, the poor quality of cystoscopic pictures, and the cautious attitude of physicians toward excisional biopsy in these cases. It is therefore important and challenging to find a non-invasive technique for examining the mucous membrane of the urinary bladder in children.
Our patients were initially diagnosed based on clinical and cystoscopic data. Although one patient showed no clinical and endoscopic evidence of any inflammatory process in the urinary bladder, our OCT investigation revealed various congenital abnormalities in the urinary system. In two cases, EOCT detected chronic cystitis in the remission stage. In another two cases, signs of active catarrhal fibrous cystitis was detected while, in another four cases, cystic cystitis was detected.
When examining the mucous membrane of the urinary bladder, an OCT endoscopic probe was inserted into the operative channel of a surgical cystoscope. The bladder was filled with an appropriate dose (150–200 ml) of sodium chloride solution to ensure stretching. This stretching kept the tissue surface even and also caused in-depth flattening of the hollow structures (e.g., cysts and blood vessels).
When there is no inflammatory process in the mucosa of the urinary bladder (Fig. 1), the transitional epithelium (TE), being only 15–25 μm in thickness, can be vizualized in our OCT images only approximately, not clearly differentiated. The highly backscattering lamina propria (LP), in clinical practice more frequently called the subepithelial layer, is approximately 150 μm thick. The submucosal (SM) layer is much less light scattering than the LP and has a well pronounced stratified structure of approximately 300 μm thickness. Underlying this submucosal layer is a weakly backscattering muscular layer. Thus, the overall thickness of the normal mucosal and submucosal layers of the child’s urinary bladder appears to be approximately 500 μm. In the subepithelial layer, low-scattering blood vessels (BV) can be clearly seen in the image.
The active stage of chronic catarrhal fibrous cystitis (more than six month’s duration) affects the submucosal layers more than the epithelial layer. This stage is characterized by marked edema of the stroma. This tissue change, imaged well by EOCT (Fig. 2), evidences some thickening of the LP and significant swelling of the submucosal layer, which becomes more transparent, loses its stratified structure, and increases its thickness up to 650–700 μm.
The active stage of chronic cystic cystitis is also imaged well by EOCT. However, the image is more diverse in this case and is dominated by the presence of serous fluid filled cysts. These cysts may be located directly under the epithelium. (Fig. 3b). The epithelium above these cysts is significantly thickened (60–70 μm) and hence can easily be resolved. The edema affects not only the epithelium, but the subepithelial and submucosal layers as well. The cysts are usually multiple. The epithelial surface may be covered with fibrin which, together with the epithelium, is 120–130 μm thick (Fig. 3c). In another patient, the cysts were located in the submucosal layer (Fig. 3d). They contributed some distortions to the mucosa, elevating its surface, much as in the previous case.
Prolonged chronic cystitis (more than two year’s duration) in the remission stage (Fig. 4) is characterized by distrophical and atrophical processes in the epithelium which are difficult to visualize in the OCT image. At the same time processes of sclerosis and fibrosis prevail in the connective tissue of the subepithelial and submucosal layers. This is seen in the images by increased backscattering from these structures. Increased vascularization is also a characteristic morphological sign of mature cystitis. This vascularization is evidenced in the images by multiple, low-scattering cavities with different sizes (from 60 to 800 μm) in the subepithelial and submucosal layers. It is of interest to note that, due to liquid distension of the urinary bladder, blood vessels may be substantially flattened and appear in cross section with a large aspect ratio. The boundaries of these vascular cavities are rather sharp, distinguishing them from the serous cysts previously shown. Longitudinal OCT scanning of a vessel allows observation of a flask-like venules expansion characteristic of urinary bladder mucosa (Fig. 4c).
In summary, the signs of active inflammation in the urinary bladder of children, which can be detected by EOCT, are the following: edema of the subepithelial and submucosal layers (with obvious change in their structure), appearance of serous cysts in the subepithelial and submucosal layers, and fibrin deposition on the epithelial surface. These signs distinguish the active stage from the remission stage which is characterized by atrophy and dystrophy of the transitional epithelium, sclerosis of the subepithelial layer, and excessive vascularization of the epithelial and subepithelial layers.
EOCT imaging of other origins has not yet been accomplished, but there are no reasons to believe that similar signs will not be found.
3. EOCT of the larynx
The larynx is an organ easily amenable to EOCT imaging, particularly as regards diagnosis to tumor-like lesions. The rate of tumor formation in the larynx is very high and these tumors represent 5–7% of all malignant tumors in humans . This high rate is caused by the frequent tension and traumatization of the ligamentous apparatus in the larynx. Timely cancer diagnosis, providing an opportunity for organ-preserving treatment, is quite possible since one of the early signs of the disease is a hoarseness which often causes the patient to consult a physician.
The upper and middle portions of the larynx (including the epiglottis, the vestibular and vocal folds, the anterior and posterior commissures, and the superior aperture of the laryngeal ventricle) are most frequently affected by tumors and, fortunately, are easily accessible by EOCT. All of these portions of the larynx are covered by stratified squamous epithelium. The thickness of this epithelium is minimal (50 μm) in the lower larynx on the anterior commissure (Fig. 5a) and the subglottic space (Fig. 5b), approximately 100 μm thick in the vocal fold (Fig. 5c), and maximal (up to 200 mμ) in the vestibular folds (Fig. 5d) and posterior commissure (Fig. 5e). In the region of the piriform sinus, EOCT can detect glandular ducts in the connective tissue stroma (Fig. 5f) and large blood vessels in the vestibular folds (Fig. 5d). Low-scattering cartilage (C) can be identified in the image of the epiglottis (Fig. 5g) and the mucosa in the region of the arytenoid cartilage (Fig. 5h). Thus, it can be seen that healthy mucosa of the larynx has some specific inherent structural features that are easily differentiated by EOCT.
EOCT capabilities for imaging the larynx were studied in fifteen patients with various abnormalities in the vocal folds. Clinically, carcinoma was diagnosed in ten of these patients, vocal nodules were diagnosed in another four, and a glandular mucosal cyst in the region of the vocal fold was diagnosed in a final patient. Four of the ten patients with carcinoma of the larynx were receiving a course of distant gamma therapy and were monitored by EOCT to determine, in vivo, the effect of ionizing radiation on larygeal tissues. EOCT explanation of the mucosa of the larynx was accomplished by inserting the EOCT probe through the lumen of a laryngoscope.
EOCT demonstrates with excellent reproducibility that carcinoma of the larynx has no tomographically differentiable structure and is image visualized as a homogeneous highly backscattering tissue. EOCT can also detect boundaries between a tumor and normal tissue (NT) not often seen with the human eye (Fig. 6).
The vocal nodule is known to be characterized morphologically by fibrinoid changes and stroma edema. These signs are observed in the EOCT images as dark regions with “fuzzy” boundaries (Fig. 7). The epithelium above the tumors is preserved and often not thickened (60–80 μm).
Cysts of mucous gland in the region of the vocal fold are difficult to diagnose in vivo. However, in the EOCT image below, such a cyst is seen as a large (over 2 mm), clearly delineated shadow, 300 mm below the surface (Fig. 8).
The results of in vivo EOCT monitoring of the laryngeal mucosa of the vocal fold during gamma-radiation treatment for carcinoma are interesting. Morphologically, it is known  that such treatment results in papillomatous hyperplasia, metaplasia of the epithelium, hypertrophy of the mucous glands, edema, sclerosis and radiation fibrosis of the connective tissue stroma. The EOCT images correlate well with the morphological information (Fig. 9).
In summary, differentiable tomographical signs characterizing neoplasms of the larynx of different origins, demonstrate that EOCT can be applied usefully in vivo to differential diagnosis of tumors, determination of tumor borders, guiding excisional biopsy, and monitoring tissue during the course of distant gamma-therapy.
4. OCT in gynecology
Our previous papers on the gynecologic applications of OCT have demonstrated its capabilities for evaluating the state of mucous membranes in various parts of the female genital system [13–15]. Information on the structure and size of epithelial layers in the female genital organs is important from several standpoints. Such information can be indicative of the development of pathological processes or can provide additional knowledge about the functional states of the female as in, for example, hormonal imbalance.
The uterine cervix was chosen for OCT study in the paper for a number of reasons. First, the standard techniques used in modern gynecology to diagnose uterine cervical cancer are not infallible. Misdiagnosis is still quite frequent and its frequency has not decreased in the past several years. Second, since uterine cancer affects women of reproduction age, organ-preserving treatment should be preferred, a treatment only possible during the early stage of the disease. Therefore, new, effective, non-invasive diagnostic techniques are much needed in this area. The stratified squamous epithelium which covers the uterine cervix is easily imaged by EOCT, providing evaluation of the basal membrane and the underlying stroma [13,14].
One hundred gynecological patients were examined in the EOCT study of the uterine cervix. These patients were also examined at approximately the same time with standard colposcopy, cytology, and microscopic histology. For several gynecological pathological conditions, tissue images were obtained of background “processes”, precancer, and different stages of uterine cervical cancer. Figure 10 is an EOCT tomogram of a uterine cervix demonstrating the characteristic features of the transformation zone with overlapping layers of cylindrical and metaplastic epithelium, evidencing ducts of open glands and formation of closed glands [19–21]. Figure 11 is an EOCT tomogram of severe dysplasia (CIN II-III) of a uterine cervix which correlates well with histological data taken from this same region. It also correlates well with well-known morphological changes at the interface between epithelial layers and stroma, where the epithelium forms so-called “pillars” and “blocks” while the stroma attempts to push its way toward the surface as vertical columns [19, 20].
EOCT can demonstrate “in vivo” the disappearance of normal structural mucosal patterns resulting from invasive cancer of the uterine cervix (Fig. 12). More importantly, EOCT can detect the boundaries of the pathological process even better than standard colposcopy. EOCT provides objective data concerning the location of the transition from normal to pathological epithelium (Fig. 13). Such information is indispensable to practicing physicians since it allows them to accurately localize pathological areas, within the normal tissue, so as to perform precise biopsies with adequate excision of the pathological zone.
To evaluate the capabilities of EOCT to monitor in vivo the effectiveness of cancer treatment, a dynamic (i.e., real time) EOCT study of a case of cryodestruction of a uterine cervix with ectopia was undertaken. Tomograms were made at time intervals (from a few minutes to six weeks) after the cryoapplication. According to known morphological information , immediately after cryotherapy intensive vasodilatation and fragmentation of cells occurs, leading to swelling of the epithelium and edema of the stroma. Twenty-four hours later, the development of cryonecrosis and the disappearance of the surface epithelium begins. During the next six weeks, healing takes place. Treatment is deemed adequate if the area destroyed is localized to that just beyond the pathological zone. It is known that the zone of necrosis differs from the area of freezing. The size of this zone depends on the type of biotissue, the type of pathological process, instrument modification, the cryogen, and the choice of parameters of treatment . As a result, it is very difficult to predict the area of development of this zone of necrosis. The EOCT tomograms (Fig. 14) clearly demonstrate all changes in the uterine cervix caused by cryoapplication.
EOCT was also used to monitor electroexcision and laser vaporization. The EOCT images to follow were recorded at the borders of destruction areas resulting from these treatments. Fig. 15 exhibits images of the same location in the cervix, obtained two and six weeks after electrosurgery. After two weeks, a zone of coagulation necrosis bordered by normal epithelium may be seen with signs of disintegration of surrounding tissues due to reactive inflammation. After six weeks, complete recovery of the epithelial layer is indicated. Fig. 16 exhibits images of the same location in the cervix, two days and three weeks after laser vaporization. After two days, a highly scattering area corresponding to necrosis can be seen with signs of liquid accumulation in surrounding areas. After three weeks, the same area evidences healing, exhibiting normal stratified squamous epithelium. The changes herein imaged in vivo with EOCT are in accord with well known data regarding the healing process after these types of treatments .
The in vivo structural, mucosal information obtainable with EOCT can be used for assessment of the functional states of the whole organism. In one of our previous papers , tomograms of the endometrium of females of differing ages were presented. However, the hormonal activity of hypothalamohypophysial-ovarian system is known to influence not only the state of endometrium but also the state of the mucous membranes of other female genital organs. For example, when the concentration of estrogens decreases in older-aged women, the stratified squamous epithelium becomes atrophied, the superficial cell layers are practically absent, the mucosa is represented by basal and parabasal cells, and, therefore, the epithelial thickness is significantly reduced. On the other hand, in hyperestrogenia the number and size of epithelial cells are increased, glycogen is accumulated in the cells, all of which leads to thickening of the mucous membrane . EOCT images of the cervix clearly differentiate the epithelial differences between a normal older-aged woman and a young woman with clinically pronounced hyperestrogenia (Fig. 17). Functional epithelial differences can also be seen between the EOCT images of the cervix of non-pregnant vs. pregnant women (Fig. 18). It is known  that, during pregnancy, hypervasculization of the cervix, extracellulation of liquid, and disintegration of collagen fibers occur. This knowledge helps explain the occurrence of a large number of dark spots and horizontal stripes in Fig. 18b.
In summary, it is evident that EOCT is capable of “in vivo” monitoring of the mucous membrane of the female genital organs for the purpose of obtaining additional information on hormonal activity.
The mucous membranes of female genital organs are “targets” which reflect the functioning of the hormone producing glands and, in particular, the growth of follicles. Thus, EOCT images of the ovaries at different stages of follicle development are of particular interest. To obtain these images, OCT was combined with laparoscopy. A young female patient with suspicion of ovarian cancer was examined with standard laparoscopy in parallel with OCT, and an ovarian fibroma was diagnosed. The tomograms obtained from a normal part of the ovary demonstrate formations resembling follicles (Fig. 19a), while tomograms of the fibroma reveal complete lack of structure. Tomograms obtained from the Fallopian tube and the anterior wall of the abdomen are presented in Fig. 19 b and c.
Our EOCT system has been demonstrated to be a useful technology for examining and monitoring the structure, and associated functional changes therein, of the mucosa of internal organs. More specifically, our EOCT system has been demonstrated to be particularly useful for guiding the performance of excisional biopsy and surgical and non-surgical treatment of these organs, for obtaining additional evaluation information on the functional states of the human body, and for monitoring of post-operation recovery processes.
EOCT has been demonstrated to be particularly well adapted to imaging of organs covered by epithelium that is separated from the underlying stroma by a smooth basal membranes (e.g., urinary bladder, larynx, and uterine cervix). Laparascopic OCT was demonstrated successfully herein for the first time.
The authors are grateful to Professor Ya I. Khanin for his support of this work and to the staff and management of the Nizhny Novgorod Regional Hospital and Nizhny Novgorod Medical Academy for the opportunity to conduct this research study. The authors are also indebted to M.Chernobrovtseva and L.Kozina for their help in the preparation of the original manuscript and to A.Kraev and J.A.Warren, Jr., D.M.D. for revising this original manuscript for publication in English. This study was supported in part by the Russian Foundation for Basic Research.
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