Research ArticleOpen Access

In vivo assessment of structural changes of the urethra in lower urinary tract disease using cross-polarization optical coherence tomography

Elena B. Kiseleva

http://orcid.org/0000-0003-4769-417X

Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Square, 603005, Nizhny Novgorod, Russia

E-mail Address: kiseleva84@gmail.com

Corresponding author.

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Alexander A. Moiseev

Institute of Applied Physics Russian, Academy of Sciences, Ulyanova Street 46 603950, Nizhny Novgorod, Russia

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Anton S. Kuyarov

Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Square, 603005, Nizhny Novgorod, Russia

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Muhammat A. Molvi

Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Square, 603005, Nizhny Novgorod, Russia

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Grigory V. Gelikonov

http://orcid.org/0000-0002-0798-4570

Institute of Applied Physics Russian, Academy of Sciences, Ulyanova Street 46 603950, Nizhny Novgorod, Russia

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Anna V. Maslennikova

Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Square, 603005, Nizhny Novgorod, Russia

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, and

Olga S. Streltsova

http://orcid.org/0000-0002-9097-0267

Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Square, 603005, Nizhny Novgorod, Russia

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https://doi.org/10.1142/S1793545820500248Cited by:6 (Source: Crossref)

Abstract

The paper presents the results of a study of the female urethra in cases of urethral pain syndrome (UPS) and inflammatory diseases of the lower urinary tract using cross-polarization optical coherence tomography (CP OCT). Urethral wall structure was studied in 86 patients; 233 CP OCT images were collected. A comparative qualitative analysis of three groups of CP OCT images — “norm”, “Inflammation” and “UPS” — identified that despite the absence of a clear inflammatory factor in the patient’s examination, the urethral tissues in UPS were in an altered state. The changes in the urethral wall with UPS and in cases of inflammation were similar. Using a point scale, three experts independently performed visual scoring of the CP OCT images. Three parameters: epithelial contrast, cavities and the minimum signal depth in the co-channel were evaluated. It was found that, individually, the parameters correlate only weakly with the diagnosis. Area under the receiver operating characteristic (ROC) curve was from 0.51 to 0.78. The joint use of a number of visual signs has a greater diagnostic value than the use of the criteria individually. Area under the ROC curve using the developed cumulative criterion reached up to 0.87–0.89. This study could form the basis of a scoring system for assessing the state of the urethral tract using CP OCT images in real time. The CP OCT method provides information on the state of urethral tissues that cannot be obtained with traditional cystoscopy.

Keywords:

1. Introduction

Modern information and technological support for the process of diagnosis and treatment, as well as for the monitoring of pathological conditions of various origins, are based on analysis of medical images obtained using a range of imaging methods. This approach is of particular importance in the case of diseases that are manifested as subjective symptoms (patient complaints) but that do not present clear objective symptoms (for example, tissue injury or inflammatory processes), or changes in laboratory parameters (absence of infections). It is this group of diseases that includes a pathological condition — urethral pain syndrome (UPS) that is considered as part of a complex of chronic pelvic pain pathologies.^1,2 According to Ref. 1, every 3–4 women periodically complain of pain in the urethra, or pelvis, or of discomfort during urination, or sexual activity. Often, long-lasting complaints lead to restrictions on professional activities, problems in family relationships (including sexual), temporary or permanent disability.¹ UPS is characterized by persistent or recurrent pain in the urethra in the absence of confirmed infection or other obvious local pathological changes. Clinical guidelines for chronic pelvic pain developed by experts at the European Association of Urology (EAU) state that UPS is a polyetiological disease that requires a multimodal approach to the diagnosis and management of treatment.² According to this classification, UPS may be a form of bladder pain syndrome.

The mechanisms underlying bladder pain syndrome and chronic pelvic pain in general are currently being discussed.^1,3,4,5 The cause of pain in UPS can be a violation of innervation processes, changes in the work of nerve synapses, tissue ischemia in the pelvis, etc. It is believed that the main type of pain in chronic pain syndrome (in our case, in UPS) is dysfunctional pain arising in the absence of activation of nociceptors (“pain receptors”) and visible organic damage, including lesions of the nervous system.¹

At present, it has been proven that one of the leading causes of any inflammatory diseases of the bladder is the dysfunction of its protective barrier — epithelium.^6,7 A close relationship between embryonic development and neighboring topological location of the urethra and urinary bladder, covered with urothelium, makes the presence of the same reasons in origin and progression of UPS as in the interstitial cystitis possible. The damage mechanism in interstitial cystitis has been studied in detail: there are defects in the urothelial glycosaminoglycan layer, which might expose submucosal structures to noxious urine components^8,9,10,11 and a consequent cytotoxic and pain effect.^12,13 A chronic inflammatory process with subsequent fibrosis of the bladder tissue is supported, and its capacity is reduced.¹⁴

At the same time, an interrelation between submucosal fibrosis of the bladder and the presence of chronic infection foci¹⁴ or chronic tissue ischemia^15,16 is not excluded. Accordingly, an atrophy of the epithelium can be secondary. In the pathogenesis of some types of chronic pelvic pain, changes in blood flow impairment in the pelvic area (pelvic ischemia)¹⁷ along with innervation disorders^3,18 have been recorded. It is likely that against a background of disorders affecting the pelvic floor innervation and blood supply, the structure of the urethral wall tissues may also alter. It may include changes in the thickness of the epithelial layer and the quality of the subepithelial structures. Obviously, to understand the extent of tissue changes and diagnose the UPS a method for in vivo imaging of the internal structure of the urethral wall is required.

In the routine of a doctor’s practice, there are currently no methods available for such an investigation. Physical examination does not detect noticeable tissue changes and obvious local pathological processes. It can only help to localize the area of pain. Evaluation of periurethral structures can be performed by using cross-sectional modalities such as ultrasonography, magnetic resonance imaging, and computed tomography. Several imaging modalities play an important role in detecting pathology of the male urethra. Thus, traumatic injuries, inflammatory and stricture diseases can be detected by retrograde urethrography. In addition, assessment of the thickness and length of bulbar urethral structure can be performed by sonourethrography. Voiding cystourethrography and magnetic resonance are frequently used to evaluate urethral diverticula in women.¹⁹ However, all of these methods are used to exclude other pathologies of the urethra. It can confirm the diagnosis of UPS, but it does not allow one to look into the pathogenesis of the disease. Establishing the causes of the onset and progression of UPS presents difficulties.

A promising method for real-time visualization of the urethral tissues is optical coherence tomography (OCT).^20,21 As a method of noninvasive and label-free in vivo imaging, OCT has a spatial resolution of about 10–15 microns with a scanning depth of up to 1.5mm. OCT refers to the methods of so-called mesoscopy and allows characterizing changes in the normal tissue structure during the development of pathology. This is available at the level of the general tissue architectonics based on the differences in tissues backscattering properties. If tissue components exhibit cross-scattering or birefringence (for example, collagen or myelin fibers), they can be analyzed separately by using polarization-sensitive modality of OCT,²² including cross-polarization (CP) OCT.^23,24

Despite significant worldwide experience in applying the OCT method in many fields of medicine, including urology, this study reports its first use for investigating the walls of the female urethra in patients with UPS. Until now, the OCT has been applied for differentiating inflammatory and tumor processes of the bladder,²⁴ detecting prostate cancer for determining the boundaries of resection,²⁵ and cancer of the ureter.²⁶ In this work, the use of CP OCT for studying urethral tissues allows us to solve the important clinical task of finding an instrument for in vivo imaging of the urethral structures such as epithelium, connective tissue stroma and vascular network. Real-time visualization of urethral wall may help to differentiate pathological conditions of the urethra itself and in the bladder, and to make the final diagnosis and choose the treatment. Thus, the importance of the in vivo acquisition and operational analysis of CP OCT data in patients with UPS is beyond doubt.

The aim of this study was to determine the capabilities of the CP OCT method for the in vivo assessment of structural changes in urethral tissues in cases of UPS and to develop easy-to-implement scoring system, based on visual characteristics of the OCT image, which can assist a physician in differentiation between normal and pathological tissues. We believe that such scoring system can not only be used for diagnostic purposes, but can also facilitate a better understanding of the OCT images of the urethra by the device users.

2. Materials and Methods

2.1. Patients

This study was approved by the review board of the Privolzhsky Research Medical University. Informed consent to participate in the study was obtained from the participants. The condition of the urethra was studied in 86 patients (Table 1): 30 of them with UPS without clinical manifestations of inflammation (“UPS” group); 43 — with inflammatory diseases of the lower urinary tract of various origins (“Inf” group); in 13 patients with stones of the upper urinary tract, but without pyelonephritis, the urethra was taken as the norm (“norm” group). The age of the patients ranged from 26 to 66 years. All patients underwent a clinical minimum of studies, including a general analysis of blood, urine, urine culture and urinary flora, as well as cystoscopy combined with CP OCT and Doppler ultrasound investigation.

**Table 1. Distribution of the CP OCT images by patient’s groups and parts of the urethra.**
				Number of CP OCT images of each part of the urethra
Group	Number of patients	Number of CP OCT images	Average number of CP OCT images created from 1 patient	Distal	Medium	Proximal
Inf	43	128	2.98	43	43	42
UPS	30	83	2.77	28	28	27
Normal	13	22	1.69	9	8	5
Total	86	233	2.48	80	79	74

Standard endoscopy for women was performed in the amount of a combined examination of the bladder and urethra. After examining the surface of the mucous membrane of the bladder, the urethral wall was studied with CP OCT at the exit when the cystoscope was removed from the lower urinary tract. It was not possible to obtain technically sufficient information using urethroscopy due to the small length of the urethra (in women 3–3.5cm) and the need to straighten its walls for renderings. Moreover, this method involves obtaining information only about the state of the surface of the mucous membrane of the urethra, which looks normal in the vast majority of cases in patients with UPS.

Biopsies from the urethra were not taken, because any biopsy can cause a deterioration in the condition of patients. It is strictly forbidden to make an unjustified biopsy in the “norm” group. In the “Inflammation” and “UPS” groups, biopsy can aggravate the existing inflammatory process or provoke a new one, cause a pain syndrome, and also lead to severe functional disorders (urinary incontinence). Besides, the condition of patients with UPS is often aggravated by severe psycho-emotional disorders. Our task is not to worsen the condition of the patient in any study and to minimize functional disorders of the traumatic genesis after manipulation. However, samples of normal urethra were taken from 5 female cadavers to acquire CP OCT images of normal tissue [Fig. 2(d)].

2.2. CP OCT study

The study of urethral wall tissues was carried out using an “OCT-1300U time-domain, polarization-sensitive optical coherence tomograph” (BioMedTech LLC, Nizhny Novgorod, Russia) [Fig. 1(a)], which has a replaceable endoscopic probe [Fig. 1(b)].^27,28 The device is based on common-path autocorrelator scheme^29,30 and utilized cross-polarization reception channel.^31,32 It is approved for clinical use (product license No̱FCP 2012/13479 of 30 May 2012) and has the following characteristics: the source of radiation is a superluminescent diode with a working wavelength of 1310nm, a spectrum width of 100nm, an axial resolution of 15 $μ$ $μ$ m, a lateral resolution of 25 $μ$ $μ$ m and a radiation power of 3mW.³³ When scanning tissue at depth, a depth scattering profile or A-scans of both co- and cross-polarizations are obtained. 2D images are constructed from the A-scans during 1D transverse scanning. The use of polarized radiation as the probing light allows the construction of two conjugated OCT images: an initial (co-polarization) image, and one orthogonal to the initial image (hence “cross-”) polarization, and this arrangement is crucial for the optical separation of nonfibrous (cells) from the fibrous (collagen-containing) tissue component.²⁴ The two OCT images obtained in co- and cross-polarization in the working window of the program are combined into one CP OCT image.

Using an endoscopic forward-looking probe with an external diameter of 2.7mm, and 2D scanning [Fig. 1(b)], 233 CP OCT images of the urethra (its proximal, middle and distal sections) were obtained (Table 1). The total duration of the CP OCT studies in each patient took no more than 3–5min. The results of the CP OCT image analysis of the bladder neck are not presented in this paper.

In the “UPS” group, the number of analyzed CP OCT images amounted to $n = 83$ $n = 83$ ; for the “Inf” group $n = 128$ $n = 128$ ; and for the “norm” group $n = 22$ $n = 22$ (Table 1). We suggest that a comparison of the results of the CP OCT examinations of two groups of patients — the “UPS” and “Inf” groups, will allow us to get closer to understanding the pathogenetic aspects of the causes of pain in the urethra in any particular patient complaining of UPS.

The color scale of CP OCT images is customizable. The data on patients were collected by two urologists within two years. They adjusted the color scale in the CP OCT images based on their preferences. Therefore, the image brightness is scaled differently for some images. The difference in image appearance was considered another noise source, since different image settings were randomly distributed across the evaluated classes.

2.3. Visual assessment of the CP OCT images

The following goals were set for the visual assessment of the CP OCT images: (1) to compare the image characteristics of the three studied groups and outline the differences between them (in particular, UPS versus norm); (2) to evaluate selected features by scoring system for subsequent correlation with an established diagnosis, as well as to construct a linear combination of the selected features, allowing any diagnosis to be made based on the summation of this combination.

To identify features for scoring, CP OCT images in normal state were taken as starting point and they were compared with corresponding histology. According to histology [Fig. 2(d)], the tissues of the urethral wall are arranged in layers, forming, respectively, the epithelium, lamina propria and muscular layer.³⁴ For clarity, the structure of the urethral wall is presented schematically [Fig. 2(c)]. The proximal part of the urethra is covered by urothelium; medium and distal parts are lined by stratified squamous epithelium. In the distal and medium urethral segments, many gland-like lacunae, the simple invaginations of epithelium, are present [Figs. 2(a)–2(c), green arrows]. The underlying lamina propria is a loose connective tissue with abundant collagen and elastic fibers, and numerous thin-walled venous plexuses (Fig. 2, purple arrows). As can be seen from the example of CP OCT image of the urethra [Figs. 2(a) and 2(b)], all these structures have different scattering and polarization properties, allowing their visual assessment to be carried out with a certain degree of accuracy.

Fig. 2. Cross-sectional anatomy of the normal female urethra and parameters for visual scoring of the CP OCT images. OCT image in co- (a, e) and cross- (b, f) polarizations and corresponding histology through the urethral wall (d) with a scheme (c) showing the anatomical layers. In CP OCT images (a, b): the green curved line indicates the boundary between the epithelium and lamina propria; the blue curved line indicates boundary between the lamina propria and muscular layers. Identification of the lamina propria is possible due to increased signal brightness of this layer in the cross-polarization image compared with the underlying muscle layer. In CP OCT images (a, b) gland-like lacunae is marked with green arrows; numerous venous plexus can be seen in lamina propria (purple arrows). CP OCT images (e, f) are labeled for visual scoring: parameter #1 — epithelium: its presence and border contrast with lamina propria; parameter #2 — number of large cavities; parameter #3 — minimum and maximum depths of the useful signal in co- and cross-polarizations excluding epithelium. This value is determined as a percentage of the image depth from the upper border of the lamina propria to the lower minimum and maximum signal border with noise; if there is a mismatch with the marks on the scale and not the half in between, the mean that is closest to the measured one is taken.

Three characteristics were chosen for the scoring, and a simplified system for the assessment of these was developed (Figs. 2 and 3):

Fig. 3. Examples of CP OCT images of the urethra from the training set for visual scoring. Yellow arrows indicate large cavities. Levels of the minimum and maximum depths of the useful OCT signal in each polarization are marked with yellow solid lines and yellow dotted lines, respectively. Black double-sided arrows indicate which part of the image is considered to be within the minimum and maximum depths of the useful OCT signal in each polarization.

(1)

The presence of the epithelial layer and the contrast of the epithelium-connective tissue border. This parameter was denoted as “Contrast” and determined on a discrete scale of three values:

—

The epithelial layer is visible along the entire transverse coordinate of the image; the border with the connective tissue layer is clear and contrasting (value “1”) [Figs. 2(e) and 2(f), area marked with green line and number 1; Fig. 3(a)].

—

The epithelial layer is distinguishable, but its contrast with the connective tissue layer is low; the border is fuzzy; it is not visible along the entire transverse coordinate of the image (value “0.5”) [Fig. 3(b)];

—

The epithelial layer cannot be detected (value “0”) [Fig. 3(c)].

In terms of pathophysiology, we assume that the value “1” means normal state; “0.5” indicates an inflammatory process (exudate accumulation in connective tissue) often with concomitant hyperplasia of the epithelium and “0” implies epithelium atrophy.

(2)

The presence of large cavities (“Holes”), which can correspond to relatively large vessels (blood and lymphatic) and gland-like lacunae. Formations with contrasting boundaries that are clearly distinguishable in the image in co- or cross-polarization, or in both images, were considered as large cavities [Figs. 2(e) and 2(f), areas marked with purple color and number 2; Figs. 3(a) and 3(b), yellow arrows]. Cavities with a semiaxis ratio of more than 4 [Figs. 4(f) and 4(h)], as well as cavities smaller than 20 $μ$ $μ$ m, were not included. This feature was assigned values “1”, “2”, etc. depending on the number of cavities observed [Fig. 3(a), yellow arrows]. In their absence, “0” was recorded [Figs. 3(b) and 3(c)].

Evaluation of this parameter suggests that the higher value represents the state closer to the norm; the lower value (up to 0) more likely indicates the state of tissue pathology. The decrease in the value can be caused by two reasons: a reduction in the number of gland-like lacunae formed by the epithelium or by a change in the shape of the lumen of vessels due to fibrosis of the connective tissue. In this case, the lumen of the vessels becomes flatter, and they pass from the category of cavities into the category of ellipsoidal-shaped lines and also cease to be taken into account in this criterion.

(3)

The depth of the useful signal below the epithelium (as a percentage of the total image depth excluding epithelial layer). Four components were evaluated — the minimum and maximum depths for each of the two polarizations [Figs. 2(e) and 2(f); Fig. 3]. Only one of the four with the biggest Pierson correlation with the diagnosis was intended to be used in the final score to prevent domination of the depth parameters in the criterion. This parameter was the minimum signal depth in the co-channel. It was used in developing a cumulative scoring criterion.

A visual assessment was carried out by three experts. Expert #1 — an intern with six-month training in the CP OCT image interpretation, Expert #2 — a researcher at the OCT lab with multiple years of CP OCT experience and Expert #3 — practicing physician with multiple years of CP OCT experience. Experts #1 and #2 performed their scoring blinded, while Expert #3 participated in the data collection and patient’s treatment, thus could not be considered as a blind expert. However, all of the experts made their score before the final cumulative criterion was derived; thus, none of the experts knew beforehand which score will affect the resulting diagnosis to be positive or negative. Before completing their evaluation table for the CP OCT images, experts had been trained using a training exercise.

2.4. Cumulative parameter development

To develop a cumulative scoring criterion based on the qualitative assessment of the CP OCT images, visual scores of the Expert #1 were analyzed. The aim of the criterion was to distinguish between images of normal tissues from those of pathological tissues (both in the inflammatory process and in UPS). The criterion was supposed to be the weighted sum of the individual visual scores. Weight factor of $+ 1$ $+ 1$ was assigned to the visual criteria, which has the positive Pearson correlation with the outcome and the weight factor of $- 1$ $- 1$ was assigned to those with the negative Pearson correlation. To prevent depth of the image from being the most dominant parameter, only one of four depth parameters was included in the resulting criterion (namely the minimum depth in the co-channel, as one that provided the maximum Pearson correlation with the outcome). We believe that such an oversimplified approach can reduce the probability of the overfitting, which was a concern due to the small size of the dataset.

The cumulative criterion obtained by the method described in the “Materials and Methods” section, based on an analysis of the first expert’s responses was :

{C r i t = M i n d e p t h}_{c o} - H o l e s - C o n t r a s t,

where Crit — calculated cumulative criterion, Min depth $_{c o}$ $_{c o}$ — minimum signal depth in the co-channel, Holes — number of cavities visible in the CP OCT images, Contrast — the value of the visual assessment of the contrast of the epithelium (taking values of 0, 0.5 and 1). Small values of the cumulative criterion correspond to the norm, large values correspond to pathology. Thus, considering all images with values of the cumulative criterion above the threshold pathology, it is possible to obtain a diagnostic criterion and calculate its sensitivity and specificity. The scores of the Experts #2 and #3 were effectively used to evaluate the resulting criterion.

The effectiveness of each visual parameter and the cumulative criterion for differentiating “norm” versus “Inf”, “norm” versus “UPS” and “UPS” versus “Inf” was determined using the area under the receiver operating characteristic (ROC) curve. This curve for a numerical criterion is a set of “sensitivity” and “1-specificity” values plotted on a plane for the different threshold values for this criterion that separates any two states of interest. An ideal criterion that accurately separates two states from each other has an area under the ROC curve of value: 1. A set of random numbers that are not related to the diagnosis will have an area under the ROC curve of 0.5.

2.5. Reproducibility assessment

The reproducibility of the estimates between the experts was evaluated using the intraclass correlation coefficient³⁵ for the continuous scores (number of the large holes and the minimal signal depth in co-polarization) and using the Cohen coefficient kappa³⁶ for the categorical contrast score. Both coefficients vary within 0–1, where 0 corresponds to a lack of reproducibility, and 1 to full reproducibility.

3. Results

3.1. Cystoscopic findings

Using cystoscopy, as is included in the clinical protocol, only the mucous membrane of the bladder undergoes visual manifestation of change. It is impossible to assess the urethra. In all patients of the “UPS” group, the mucous membrane of the bladder was unchanged — remaining shiny and pale pink; only in 28.6% of cases was there slight hyperemia in the area of the bladder triangle and neck. Therefore, for in vivo evaluation of the urethra itself, it was proposed to use the CP OCT method.

3.2. Comparative qualitative evaluation of the CP OCT images of urethral wall

Figures 4(a)–4(c) show typical CP OCT images of the normal urethral wall in its three sections. As with the bladder wall, in the images in co-polarization [Figs. 4(a1), 4(b1), 4(c1)], the epithelial and underlying lamina propria layers (represented mainly by connective tissue) are distinguishable, since the components of the connective tissue create much greater scattering than do the epithelial cells. The signal from the third, muscle layer is reduced. In cross-polarization, the OCT signal is mainly determined by the collagen and elastic fibers of the connective tissue, and therefore only the lamina propria is clearly visible in this image, while the epithelium is not visualized and the muscular layer is barely visible [Fig. 4(a2), 4(b2), 4(c2)]. The gland-like lacunae like epithelium give a low signal level in the image in co-polarization and did not demonstrate cross-scattering [Figs. 4(b) and 4(c) green arrows]. Vessels of the venous plexus are multiple in lamina propria and can be distinguished as dark cavities of different shape [Figs. 4(a)–4(c), black arrows].

Fig. 4. CP OCT images of urethral segments in the studied groups. 1st row — “N” group, 2nd row — “Inf” group, 3rd row — “UPS” group. The left image from the pair of CP OCT images corresponds to co-polarization (a1, b1, c1, d1, e1, f1, g1, h1, i1), the right image — to cross-polarization (a2, b2, c2, d2, e2, f2, g2, h2, i2). (a–c) — normal epithelium forms gland-like lacunae (green arrows), numerous venous plexus can be seen in lamina propria (black arrows). The vessels of the venous plexus have the largest lumens in the distal part of the urethra (c). In inflammatory diseases (d–f) and UPS (g–i), epithelium atrophy as well as increased thickness and signal intensity in cross-polarization image of lamina propria are observed in all segments of the urethral wall. The birefringence effect appears in the images in the form of a dark strip (indicated by white stars). In general, the number of cavities corresponding to venous plexus is significantly reduced (d, e, g, i) and presented as ellipsoidal-shaped lines (f, h).

According to the CP OCT results, in the structure of the inflamed urethra [Figs. 4(d)–4(f)], it was possible to identify: epithelial atrophy in 40.6% of cases; fibrosis (increase in signal brightness in the cross-channel) in 55.5% of cases and there was thickening of the second (connective tissue) layer by an average of 35–55% (determined from cross-polarization images for different sections of the urethra) compared to the norm [Figs. 4(a)–4(c)]. In UPS [Figs. 4(g)–4(i)], atrophy of the epithelial layer was detected in 20.5% of cases, fibrosis of the subepithelial structures was detected in 48.2% of cases, and there was thickening of the second (connective tissue layer) by 25–40% compared with the norm [Figs. 4(a)–4(c)]. In this case, the maximum thickening (an increase in the region of the bright signal in the cross-channel along the z-coordinate) was observed in the proximal third of the urethra (up to 200%). Thus, the changes in the urethral wall with UPS and in cases of inflammation, as detected by CP OCT, are similar. This proves that, despite the absence of a clear inflammatory factor in the patient’s examination, the urethral tissues in UPS are in an altered state, which is a consequence of processes that may result from impaired blood circulation in the pelvic area, or of pathological innervation.

3.3. Effectiveness of individual visual parameters and cumulative criterion in UPS detection

The effectiveness of the visual criteria obtained by the first expert for diagnosing urethral conditions using CP OCT images is shown in Table 2. It can be seen, that the combined use of visual criteria can significantly increase the effectiveness of diagnostics both UPS and inflammatory diseases using CP OCT images. The values of each criterion and of cumulative one are similar for differentiating “norm” and “Inf” as well as “norm” and “UPS”. Low correlation values for comparing UPS and inflammatory diseases indicate similar estimates, and hence similar tissue conditions. This is an important finding since it is believed that with UPS the tissue structure is unchanged, but we showed the opposite.

Table 2. Effectiveness of the individual visual parameters for CP OCT images of the urethra, and the cumulative criterion for differentiating between the three classes. Note that the area under the ROC curve was calculated for each of the terms of the cumulative criterion separately with the corresponding signs, which means that parameters number of cavities visible in the CP OCT images and contrast of the epithelium were multiplied by $- 1$ $- 1$ . The results for three experts are separated with a slash.
Criterion	$-$ $-$ 1*Contrast	$-$ $-$ 1*Holes	Min depth $_{c o}$ $_{c o}$	Cumulative criterion
Area under the ROC curve for groups “Inf” versus “N”	0.51/0.62/0.61	0.65/0.78/0.60	0.70/0.68/0.75	0.78/0.87/0.75
Area under the ROC curve for groups “UPS” versus “N”	0.56/0.72/0.66	0.61/0.77/0.60	0.70/0.74/0.78	0.78/0.89/0.78
Area under the ROC curve for groups “UPS” versus “Inf”	0.45/0.39/0.45	0.55/0.52/0.51	0.51/0.49/0.48	0.53/0.47/0.46

The reproducibility of the visual evaluations used in the cumulative criteria made by three experts is presented in Table 3. According to Ref. 37, for values of the intraclass correlation coefficient below 0.5, reproducibility should be considered weak, and for values of the coefficient of intraclass correlation in the range 0.5–0.75, average. Thus, the reproducibility of the proposed visual criteria for the three experts is mostly moderate, in some cases weak.

**Table 3. Reproducibility of visual criteria between experts.**
	Criteria
Compared experts	Contrast	Holes	Min depth $_{c o}$ $_{c o}$
1 and 2	0.65	0.30	0.62
1 and 3	0.55	0.49	0.58
2 and 3	0.65	0.52	0.71

The developed criterion was applied to the answers of the remaining two experts. Figure 5 shows histograms of the distribution of criterion (1), as well as error curves for the cumulative criterion obtained on the basis of the visual assessments of all three experts. It can be seen that, in spite of the fact that the criterion was developed on the basis of the analysis of the answers of only one of the experts, and also despite the merely average reproducibility of the visual estimates between the experts (Table 3), the cumulative criterion shows similar efficacy for all three experts in terms of the area under the ROC curve at the same threshold value of the criterion that separates the norm from the pathology according to the CP OCT images (Table 2).

Fig. 5. (a–c) Histograms of the cumulative criterion distribution for assessing CP OCT images of the urethra for experts 1–3, respectively for the three studied groups (“norm” — blue curve, “Inf” — yellow, “UPS” — green); (d–f) ROC curves for experts 1–3, respectively for the diagnosis “Inf” versus “norm” (red curve), “UPS” versus “norm” (black curve) and “Inf” versus “UPS” (blue curve).

It should be noted that for the introduction of a more complex criterion than was proposed in the section “Materials and Methods”, it is necessary to analyze more patients. The current work has been undertaken only to demonstrate the potential of this approach.

Based on the developed of a cumulative criterion, an express diagnosis of the urethra can be performed: both for differentiation, the norm and inflammatory changes in the urethra, and the norm and UPS. Thus, it was shown that the cooperative use of the simple sum of a number of visual features has much greater diagnostic accuracy than the use of any of these criteria separately. In addition, it was shown that the values of the criteria that do not have a reliable correlation with the diagnosis can positively influence the overall assessment. The developed approach allows objective diagnosis of the pathological changes in the urethra associated with urethral pain. It was revealed that structural changes in urethral tissues during UPS are similar to those in inflammatory diseases, even though there are no clear signs of tissue inflammation. This study can therefore form the basis of a scoring system for assessing the state of the urethral tract using CP OCT images.

Five months later, the experts perform scoring once again. The reproducibility of the results is shown in Table 4. One can see that the scores of Expert #2 demonstrate an almost perfect reproducibility, the scores of Expert #3 shows good reproducibility, while the scores of Expert #1 shows moderate or even poor reproducibility. It can be suggested that the reproducibility of the scores correlates with the experts’ experience with the OCT data, since Expert #1 had only about 6 months of such training before the first test was taken, while the Expert #2 has by far the biggest experience, since the CP OCT is the primary interest of his research. However, this theory should be thoroughly studied before any conclusive statements will be made.

**Table 4. Reproducibility of the results in re-evaluating of the CP OCT images by each expert.**
	Contrast	Holes	Min depth $_{c o}$ $_{c o}$
Expert 1	0.36	0.43	0.35
Expert 2	0.94	0.95	0.96
Expert 3	0.69	0.74	0.74

The overall performance of the derived cumulative criterion slightly changed as well. The performance of the criteria for the scoring after five months break are presented in Table 5.

Table 5. Effectiveness of the cumulative criterion for differentiating between the three classes for the scoring taken five months after the initial scoring. The results for three experts are separated with a slash.
Compared groups	Area under the ROC curve for cumulative criterion
“Inf” and “N”	0.73/0.83/0.82
“UPS” and “N”	0.74/0.85/0.81
“UPS” and “Inf”	0.48/0.48/0.55

4. Discussion and Conclusion

The diagnostic arsenal of methods for patients with suspected UPS includes a physical examination of the external opening of the urethra and adjacent tissues, a bimanual palpation of the urethra and vaginal walls on a chair, cystoscopy, as well as ultrasound research of the pelvic organs.^2,38 The diagnosis of UPS suggests the absence of any pathology during an examination.

A bimanual palpation of the urethra and vaginal walls on a gynecological chair allows determining the localization of pain (trigger point). It indicates suspicious pathology domains, for example, myofascial or gynecological component (endometriosis), which does not add anything to the diagnosis or understanding of the pathogenesis of the disease. Urethroscopy is used to look inside the male urethra,³⁹ since this procedure involves straightening the walls of the organ (irrigation urethroscopy to examine the posterior urethra), which is not possible to do adequately with a short urethra (3–3.5cm) in women. Therefore, only cystoscopy is performed in women to look for abnormalities in the bladder, while the urethra remains unexamined. In addition, the introduction of a cystoscope or urethroscope with a diameter of 18–22 French (6–7mm) into the urethra having approximately 4.7mm of internal diameter⁴⁰ often causes reactive hyperemia and it became subjectively difficult to verify a latent inflammatory process. Moreover, urethroscopy in women often requires local anesthesia, and in some cases even general anesthesia. Ultrasound for diseases of the lower urinary tract is used to exclude gynecological pathology or analysis of the venous vascular bed of the pelvis,⁴¹ and not to detect changes in the structure of the urethra. There are few studies on the urethra in case of urinary incontinence,⁴² but we did not meet with the use of ultrasound to study urethra.

From the above, it follows that OCT has obvious advantages over other tools for clinical imaging. Firstly, the method has the ability to conduct a gentle/minimally traumatic study of the female urethra. The outer diameter of the OCT probe is 2.7mm; for its insertion into the urethra, special conductors are not required, the procedure does not require the use of painkillers. Secondly, the probe can be installed at any point throughout the urethra, including examination of the bottom of the bladder adjacent to the proximal part of the urethra. Thirdly, it takes 2s to record 1 image, which allows you to conduct a study quickly (within 3–5min). This is important from a psychological point of view for the patient and labor costs for the doctor. Fourth, the method allows you to visualize the structure of the urethral wall — the epithelial and underlying connective tissue layer, including a venous plexus, in some cases a part of the muscle layer — with a resolution close to the cellular one, what cannot be made by any other method of in vivo imaging with this localization. While the rest of the methods are used in UPS to exclude the pathology of adjacent organs (UPS, by definition, is the diagnosis of exclusion), we used OCT to directly evaluate urethral tissues, which was done for the first time.

Previously, male prostatic urethra in prostate diseases was studied ex vivo by OCT.^{43,44,45,46,47} First, OCT visualization of the architectural microstructure of the prostatic urethra and the periurethral prostate with corresponding histology was made by Tearney et al.⁴³ with the long-term aim of using OCT as an adjunct to endoscopic imaging and to improve the efficiency of interventional procedures such as transurethral prostatectomy. Zagaynova et al..⁴⁶ demonstrated an OCT image of excised male urethra from its outside (striated muscle of urethral sphincter and smooth muscle of submucosa). Subsequent papers^44,47 claimed that OCT could distinguish malignancy from benign prostate tissue based on architectural differences in the tissues that showed their unique pattern in OCT images. In addition, the optical attenuation coefficient can play a role in the differentiation between stroma and malignancy; however, analysis of the attenuation coefficient obtained from the same patient did not show a significant difference.⁴⁷ It should be noted that after radical prostatectomy samples were scanned on a tissue section or through a puncture which were made randomly. Consequently, the stratification of the urethral wall was damaged, and the regions of the OCT scanning in a chaotic order contained prostatic stroma, benign glands, cystic, and regular atrophy, fibrous or adipose tissue, and malignancy.

In our study, we aimed in vivo investigation of urethral wall from the inside of the organ, inserting the CP OCT probe into its lumen. Since we analyzed changes in the structure of the urethra in benign conditions, when CP OCT images look layered in all cases. We suggested visual assessment of the several evident parameters such as the presence of the epithelium layer and its contrast with the underlying connective tissue stroma, the presence of cavities and the signal penetration depth in connective tissue. Cross-polarization channel show signal only from fiber-like structures (mainly from collagen); therefore, we are sure that we are analyzing particular connective tissue. When choosing these parameters for visual assessment, we assumed that in UPS, similar to the inflammatory process the thickness of both the epithelial and lamina propria layers, as well as the changes of quality of the connective tissue stroma (its fibrosis) can occur. Indeed, qualitative comparison of the CP OCT images in the studied groups showed that the condition of the epithelium and connective tissue structures of the mucosa in patients with UPS is not normal; the changes (epithelial atrophy and fibrosis) are similar to those in chronic inflammation. The revealed changes in the CP OCT characteristics are comparable with the results of our previous studies of urinary bladder^48,49 and urethra⁵⁰ and investigations of other groups.^51,52

Using OCT, Meller et al.⁵¹ demonstrated thinning of the epithelium in atrophic rhinitis. Pan et al.⁵² showed the partially and completely denudated urothelium following chemically induced inflammation. Similar to our study, in the paper 47 is noticed, that parallel ellipsoidal-shaped lines were unique for urethral stroma and probably caused by fibrotic tissue. Visualization of cavities features was also used in work 47 to separate benign cystic structures (benign/cystic and regular glands) in the prostatic part of the urethra. Based on histological verification, it was found that cystic atrophy was visually identified by cavities ( $> 0.5$ $> 0.5$ mm), divided by septae. The content of the cavities appears opaque due to backscattered light. Regular atrophy has smaller (0.1–0.3mm), dark, more grouped cavities than those found in cystic atrophy. Benign glands have even smaller, mostly grouped cavities ( $\leq$ $\leq$ 0.1mm). The cavities could be dark or opaque. These findings may be helpful in the future studies of female urethra.

In our previous study of urethral wall using CP OCT,⁵⁰ it was shown that, compared with the “norm” group, in the “Inf” group, changes in the epithelial layer (its hyperplasia or atrophy) are more often observed in the initial stages of the disease, after which inflammatory changes pass to the connective tissue stroma and are manifested by its fibrosis (shown as an increase in the level of the OCT signal in cross-polarization). By contrast, in the “UPS” group, at a structural level, the pathogenesis of the disease begins with changes in the connective tissue stroma (its fibrosis is also observed, which can be seen as a noticeable increase in the cross-scattering signal level, up to the appearance of the birefringence effect) with subsequent spread to the epithelial layer, most often causing its atrophy.

These findings are confirmed by studies of a potential pain-generating mechanism in UPS associated with disorders in the epithelium and connective tissue. Parsons showed that a leaky dysfunctional epithelium and subsequent diffusion of potassium into the tissue may be responsible for the pelvic pain.⁵³ Moreover, pathogenic flora can also penetrate in subepithelial structures with the urine, causing irritation of nerve receptors,⁵³ stimulating fibrosis and disruption of the microcirculation in the urethral wall. According to Chung’s data,⁵⁴ mast cells activities in chronic bladder inflammation reflect not only the severity of inflammation but also the bladder symptom presentation in lower urinary tract dysfunction. As a result, a cascade of interrelated events is initiated, resulting in a vicious, self-reinforcing cycle of persistent inflammation and recurrent injury to the urothelium.⁵⁵ Understanding the pathophysiological mechanisms of pain formation and introduction of novel imaging methods into the physicians’ practice will allow the development of effective approach to treatment planning.

Since CP OCT method covers the range of possibilities for visual monitoring of the state of the bladder during cystoscopy and provides information on the urethral tissue structure that cannot be adequately assessed with traditional cystoscopy, it is proposed that their combined use will allow the development of an algorithm for minimally invasive diagnosis of the state of the lower urinary tract, in particular, the state of the epithelium and connective tissue in cases of UPS, and the use of personalized indicators for the appropriate adaptation of therapy.

It is known that analysis of the complex of quantitative characteristics of medical images can provide more complete and accurate information about diseases than can the help in the assessment of images with the naked eye.⁵⁶ The differences revealed by such methods between several pathological conditions can be used for diagnosis, as well as for determining the prognosis of the disease and for monitoring treatment, that is, for implementing the principle of “personalized therapy”.⁵⁷ This approach initially arose in relation to the analysis of images of malignant tumors.⁵⁸ It is hoped that this study may become the basis for creating a scoring system for the degree of changes/damage to the connective tissue, depending on the severity of pain in UPS in women, as well as for conducting their clinical testing. It can be seen from Table 2 that Experts #1 and #2 benefit from the introduction of the cumulative criterion with the significant increase of the prediction accuracy, while for Expert #3 the minimal depth in co-polarization works just as well as the proposed cumulative criterion. It may suggest that based on the sample size from the study the cumulative criterion may be suggested as it at least works as good as the individual ones for some experts, while improving the diagnostic accuracy for the others. More data, first of all normal tissue images should be collected before final criterion and its performance could be evaluated. However, the present study suggests that the goal of distinguishing between normal tissues and tissues affected by UPS can be achieved by simple analysis of the CP OCT images. The proposed method could not differentiate between UPS and the inflammation, but this task can be performed by other diagnostic tools.

One should also be stressed that the proposed criterion does not work equally well on all of the experts, and the limited data in hand allows only the speculation that the performance of the criterion depends on the experts’ experience, since the expert with the highest criterion performance has the highest experience with the OCT images and vice versa. This theory will also be tested as more data will be collected.

Thus, a simple linear combination of a number of visual parameters of CP OCT images that can be selected by a specialist, allows the detection of pathological processes from these images, even if no changes can be detected with other types of clinical examination. With an accumulation of a sufficient amount of experimental data, it is possible to search for the coefficients of a linear combination of visual signs using one of the automatic methods, increasing the diagnostic accuracy of the criterion. However, at this stage of the study, such an approach could lead to so-called “retraining”, so it was decided to reduce the combined criterion to a simple sum/difference of parameters. The results of the study also demonstrate the significant role of the expert’s/future researcher’s training in assessing the CP OCT images in order to increase the reproducibility of the assessments of individual visual criteria.

Conflicts of Interest

The authors have no relevant conflicts of interest to disclose.

Acknowledgments

This work was financially supported by the the RFBR grant, project No. 19-07-00395.

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Received 31 March 2020

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