New cystoscopic diagnosis for interstitial cystitis/painful bladder syndrome using narrow-band imaging system

Authors


Tomohiro Ueda md phd, Department of Urology, Kyoto City Hospital, 1-2 Mibuhigashitakada-cho, Nakagyo-ku, Kyoto 604-8845, Japan. Email: tom-nobu@muf.biglobe.ne.jp

Abstract

Objectives:  Diagnosing the bladder lesions associated with interstitial cystitis/painful bladder syndrome (IC/PBS) is sometimes difficult for general urologists. We therefore aimed to develop an IC/PBS diagnosis method using a cystoscope with a narrow-band imaging (NBI) system that can detect mucosal angiogenic lesions.

Methods:  Fifty-two subjects suspected of having IC between October 2006 and June 2007 were included in this study. There were 49 women and three men, ranging in age from 19 through 85 with an average age of 59. First, conventional cystoscopy under spinal anesthesia was performed to examine the ulcerative lesions by a urological specialist. Then, other health care professionals made a separate observation of capillary-rich areas of the superficial layer of the bladder mucosa by cystoscopy with the NBI system.

Results:  Among the 52 patients, 37 cases were found to have ulcers by conventional cystoscopy, which were also recognized as capillary-rich brownish areas using the NBI system (100% accuracy); 13 cases were found to have NBI-positive areas without ulcer, which were coincided with those with petechial hemorrhages and glomerulations following subsequent hydrodistention; and two cases of normal mucosa were detected. Furthermore, six cases of bladder cancer (carcinoma in situ) were detected by biopsies that were obtained from the ulcerative lesions positively identified by NBI cystoscopy.

Conclusions:  Examining the urinary bladder mucosa with a flexible cystoscope with the NBI system makes it possible to easily detect ulcers of bladder mucosa and areas with angiogenesis. Therefore, it is considered that the use of a flexible cystoscope with the NBI system is highly practical for the IC/PBS diagnosis.

Introduction

Interstitial cystitis/painful bladder syndrome (IC/PBS) is a chronic disease of bladder hypersensitivity with unknown etiology. The incidence of IC/PBS varies greatly, ranging from 2 to 200 in 100 000, and the number of symptomatic patients is projected to be as high as 5000 per 100 000. Diagnosing IC/PBS is, however, left to the hands of urological specialists, as no accurate diagnostic markers are currently available, making it difficult to conduct large epidemiological studies.1

Hydrodistention of the bladder during cystoscopic examination has been used as an important means to diagnosing IC, followed by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) criteria; however, it is costly and requires spinal or general anesthesia. We have previously reported that bladder mucosa showing glomerulation and/or petechial bleeding seen during hydrodistention as well as ulcerative lesions in the IC bladder are highly associated with an elevation of angiogenic factors such as platelet-derived endothelial growth factor (PD-ECGF) and transforming growth factor-beta, which can induce immature capillary formation in the mucosal area. Therefore, in this study, we used a flexible video cystoscope (CYF-VA2; Olympus Medical Systems, Tokyo, Japan) equipped with a narrow-band imaging (NBI) system (VISERA Pro; Olympus Medical Systems, Tokyo, Japan) that can detect angiogenesis on the superficial portion of the mucosa of the bladder, and examined whether NBI-positive areas identified without hydrodistention match with those of IC-related bladder lesions such as ulcers, glomerulations and petechial hemorrhages identified by conventional cystoscope with hydrodistention in patients suspected of having IC/PBS based on their symptoms.

Methods

During the period of October 2006 through June 2007, we identified 52 patients suspected of having IC/PBS; 49 women and three men (mean age: 59 years, range: 19–85). The suspected symptoms of IC/PBS were determined by the criteria of database studies on IC provided by the NIDDK in 1987.2 IC/PBS symptoms included chronic pelvic pain, pressure, or discomfort perceived to be related to the bladder accompanied by persistent urge to void or urinary frequency, which continued for six months or longer. Approval of this study was obtained from the hospital ethics committee and informed consent was acquired from all subjects.

In all 52 patients, a urologist (T. U.) who has extensive experience in diagnosing IC/PBS performed conventional cystoscopic examination under spinal anesthesia to find ulcerative lesions in the bladder (Table 1). Thereafter, the bladder was reexamined by other general urologists using a flexible cystoscope with the NBI system. The NBI system is based on modification of the spectral features with optical color separation filter narrowing a bandwidth of the spectral transmittance, and equipped with a light source (CLV-S40Pro, Olympus Medical Systems Corp., Tokyo, Japan), and a video system center (OTV-S7Pro, Olympus Medical Systems Corp., Tokyo, Japan). A button on the control section of scope allows switching between the conventional view (white light) and the NBI view.3 For the diagnostic procedure using an NBI cystoscope, illumination at a wavelength of 415 nm extracted through a filter was used to examine the surface of the mucous membrane. The wavelength of 415 nm provides most information of capillaries within the superficial mucosa and structures on the mucosa, and capillary blood vessels are silhouetted in brown because the 415 nm wavelength is rapidly absorbed by hemoglobin.4 Therefore, in this way, actively developing angiogenesis areas observed in 415 nm light become more obvious in contrast with surrounding tissues. When such blood-vessel figures are not found, the diagnosis is that nothing abnormal was detected (Figs 1,2).

Table 1.  Subject background (52 subjects)
Mean age (range)59 (19–86)
No. sex49 female; 3 male
Mean amount per void (range)89.0 mL (50–200 mL)
Mean O'Leary–Sant symptom score (range)17.4 (9–20)
Figure 1.

Photomicrographs of ulcer lesions identified by conventional cystoscopy with white light (left) and narrow-band imaging (NBI) cystoscopy (right). (a) A 58-year-old man; (b) A 64-year-old woman. Note that an ulcerative mucosa recognized by conventional cystoscopy was clearly demarcated as a brownish area of the bladder wall with NBI cystoscopy.

Figure 2.

Photomicrographs of areas with hypervascularity identified by conventional cystoscopy with white light (left) and narrow-band imaging (NBI) cystoscopy (right). (a) A 58-year-old man; (b) A 48-year-old woman. Note that reddish mucosa recognized by conventional cystoscope was shown as a brownish area of the bladder wall with NBI cystoscopy. These hypervascular areas were coincided with those exhibiting glomerulation and/or petechial bleeding following bladder hydrodistention.

The NBI-positive areas were then biopsied and coagulated. Thereafter, a cystoscope was switched back to the conventional view and hydrodistention (80 cm H2O for 3 min) was performed to identify the areas of glomerulations and/or petechial hemorrhages. These hemorrhagic areas were then compared with the NBI-positive areas detected before hydrodistention.

In biopsied specimens, immunohistological examination and enzyme-linked immunosorbent assay (ELISA) of an angiogenic factor (PD-ECGF) were performed as described in our pervious study.5

Results

Prior to hydrodistension, NBI-positive areas were detected in 50 out of 52 subjects suspected of having IC/PBS based on their symptoms. In the remaining two cases, in which no NBI-positive areas were found, no petechial hemorrhage or glomerulation was observed during conventional cystoscopy with hydrodistention.

In 50 cases with NBI-positive areas, ulcerative lesions were observed in 37 of 50 subjects (74%) during conventional cystoscopic examination without hydrodistention performed by an experienced urologist, and these ulcer lesions were positively identified in brown when observed using the NBI system afterwards by other general urologists. In the remaining 13 cases with NBI-positive areas, which did not exhibit ulcerative lesions during conventional cystoscopic examination prior to hydrodistension, the NBI positive sites showed petechial hemorrhages/glomerulations (13 cases, 100%) when hydrodistention was performed.

In the histological examination of biopsied specimens, infiltrations of plasma cells and mast cells were seen in the NBI-positive areas in 44 of 50 cases (88%). Urothelial cancer cells indicating carcinoma in situ (CIS) were found at NBI-positive ulcerative regions in six cases (12% of 50 patients with NBI-positive areas). These histological abnormalities were not found in biopsied specimens obtained from two NBI-negative cases. Thus the cystoscopy-based diagnoses of IC/PBS were obtained in 44 cases (31 ulcerative and 13 non-ulcerative) after exclusion of subjects with CIS (n = 6) or normal findings (n = 2).

The protein level of an angiogenic factor, PD-ECGF, determined by ELISA was significantly higher in the NBI-positive areas compared with the NBI-negative areas (Table 2).

Table 2.  Rate of diagnostic accuracy of narrow-band imaging (NBI) cystoscopy
 Findings by NBI Cystoscopy
Found
(50 cases)
Not found
(2 cases)
Observation by conventional cystoscope
Ulcers found370
No. ulcers found132
Tissue diagnosis by biopsy
Inflammation440
Urothelial cancer cells such as carcinoma in situ60
Normal02
Changes seen by hydrodistention
Petechial hemorrhages/ glomerulations500
Overexpression of angiogenesis+

Discussion

IC/PBS is a disorder with symptoms of chronic pelvic pain, pressure, or discomfort perceived to be related to the bladder accompanied by persistent urge to void or urinary frequency, but shows no undeniable pathological conditions such as urinary tract infection. It is often an intractable disease and defined as a disease with nonspecific chronic inflammation of the bladder, but the etiology is unknown; therefore no clear definition of the disease is yet to be made.

Urologists worldwide now tend to diagnose IC/PBS based on their inflammatory and painful characteristics among the lower urinary tract symptoms (LUTS). However, there is no known method for detecting pathological conditions of ordinary symptoms such as urinary frequency, urgency, or bladder pain in a simple, accurate and inexpensive way. Thus IC/PBS is often confused with other disease categories such as frequency-urgency syndrome, overactive bladder syndrome, chronic pelvic pain syndrome, nonbacterial cystitis, nervous (psychogenic) cystitis, and chronic prostatitis, which could all be included in the same syndrome category, although they have essentially different clinical conditions.

Thus, cystoscopic examination with hydrodistention, which can detect objective changes in the bladder, still plays a significant role in diagnosing IC/PBS. This methodology has been included in the most well-known research criteria for IC defined by the NIDDK in 1987. According to the NIDDK criteria, IC is a bladder disease with Hunner's ulcers and/or petechial hemorrhages recognizable by hydrodistention; with bladder pain or urinary urgency; and where the following bladder diseases can be diagnosed with certainty and ruled out: infection, bladder calculi, genital herpes, bladder cancer, urethral cancer, gynecological cancer, vaginitis, tuberculous cystitis, cystitis radiation, cystitis induced by cyclophosphamide, and so on.

In Japan, the Guideline on Clinical Practice for Interstitial Cystitis was established by the Society of Interstitial Cystitis of Japan (SICJ), and diagnostic criteria for clinical purposes were announced in 2006. The SICJ's guideline defines an IC diagnosis when all three of these items are present: (i) symptoms such as urinary frequency, increased desire to void, urinary urgency, bladder discomfort, bladder pain; (ii) Hunner's ulcers or bleeding after hydrodistention of the bladder; and (iii) no other diseases or symptoms that explain the symptoms or findings above are present. The IC/PBS diagnostic criteria recently proposed by the European group of urologists also included cystoscopy to classify patients after diagnosed Bladder Pain Syndrome (BPS), a newly proposed name in place of IC/PBS.6,7

The Hunner's ulcer or lesion typically presents as a circumscript, reddened mucosal area with small vessels radiating towards a central scar, with a fibrin deposit or coagulum attached to this area. This site ruptures with increasing bladder distension, with petechial oozing of blood from the lesion and the mucosal margins in a waterfall manner. A rather typical, slightly bullous edema develops post-distension with varying peripheral extension.8 However, the diagnosis of ulcerative lesions in IC/PBS bladders is often difficult and requires expertise, although IC/PBS patients usually undergo a cystoscopic examination. Thus it is often not possible to diagnose a lesion associated with IC/PBS by cystoscopy with conventional white light unless clear ulcerative formations such as Hunner's lesions are present. Thus, the detection rate of ulcers by ordinary cystoscopy is as low as 10% to 50%9 questioning its sensitivity. In the present study, since ulcerative lesions detected during conventional cystoscopy by the experienced urologist were easily recognized as brown colored regions using the NBI system by less-experienced general urologists, this system would be useful for the accurate diagnosis of equivocal ulcerative lesions in the bladder suspected of having IC/PBS. In addition, with NBI cystoscopy, it is possible to examine the preclinical stage of ulcers or the beginning phase of mucosal abnormalities in angiogenic figures. As for Hunner's ulcers, examining angiogenic areas makes it possible to diagnose the lesions surrounding the ulcerative area, and it is also useful in determining the area for laser cauterization of ulcerative lesions.

During cystoscopic evaluation, hydrodistention is also very useful and highly sensitive for detecting petechial hemorrhages and/or glomerulation, which are the characteristics of IC/PBS bladders. It is, however, a strenuous examination for patients, as it requires them to be admitted to the hospital and have lumbar spinal or general anesthesia; it is painful after the procedure as well. In this study, we found that NBI-positive regions without ulcers detected before hydrodistention were matched with those with petechial hemorrhages or glomerulations shown after subsequent hydrodistention. These results raise the possibility that the NBI system can avoid hydrodistention to detect bladder areas, which would exhibit petechial hemorrhages or glomerulations when the bladder is distended.

Observation methods of pathological mucosal lesions using special illumination are now being put to a practical use, including narrow-band imaging (NBI), auto fluorescent imaging (AFI), and infrared imaging.10,11 The NBI system has been shown to increase the diagnostic accuracy of various cancer lesions including squamous cell carcinoma in situ of oropharyngeal mucosa, colorectal mucosal carcinoma and lung cancer.12–14 The NBI system has also reportedly been useful for detecting CIS of the bladder.15 Cystoscopy with NBI illumination uses wavelengths of 415 nm and 540 nm extracted through a filter for lighting. These two wavelengths have a high level of absorption in hemoglobin, thus improving the visibility of capillary vessels. Light at 415 nm is used to observe the superficial part of the mucosal layer, and 540 nm light is used to examine the deeper part of the layer. With the NBI system, the formation of ridges becomes obvious because of strong contrast with the surrounding areas. Even a tiny lesion that may be overlooked by an ordinary cystoscope can be detected. Tumor outlines are also shown far more clearly than with other methods. In the case of bladder CIS, mucosal irregularities and redness are visually enhanced and the boundary lines with the normal mucosa are shown, also clearly making it quite useful for determining the area for biopsy.16

However, in the past, examining LUTS using cystoscope with the NBI system had been limited only to detecting carcinomas, and it has not been reported yet that it has ever been used for diagnosing a disease other than cancer. The present study provided evidence that the use of NBI cystoscopy can be extended for the diagnosis of IC/PBS-associated bladder lesions, ulcers and other angiogenesis areas, which are likely to exhibit petechial bleeding or glomerulations following hydrodistention. We have previously reported that angiogenic factors such as PD-ECGF are increased in the ulcerative mucosal layer of IC patients.5,16 Thus it seems that cystoscopy with the NBI system that can detect angiogenic lesions in the bladder is a novel and simple tool for increasing the diagnostic accuracy of IC/PBS. In addition, it is said that 1% of patients diagnosed IC are found to have CIS.17 Thus, NBI cystoscopy accurately indicates the biopsy area for such cases, which provides urologists or other health professionals with improved cystoscopic diagnosis.

Conclusion

The results in the present study indicate that flexible cystoscopy with NBI is a simple and accurate diagnostic method for IC/PBS, and that it is less invasive and lower in cost. Furthermore, it is also useful in determining biopsy areas for pathological diagnosis including CIS, and ulcerative areas to be cauterized. We consider cystoscopy with the NBI system to be a revolutionary method to detect bladder lesions associated with IC/PBS for outpatients who complain of pelvic pain, urinary frequency and persistent urge to void.

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