Cystoscopic evaluation and clinical phenotyping in interstitial cystitis/bladder pain syndrome

Herein, we aimed to review, report, and discuss the role of cystoscopy and clinical phenotyping in interstitial cystitis/bladder pain syndrome (IC/BPS). For this purpose; a comprehensive nonsystematic review of the relevant literature was conducted. We reviewed articles published in English and indexed in the PubMed, Embase, and Google Scholar databases. Original manuscripts, review articles, case series, and case reports were taken into consideration. Data regarding the indications for, technique, and possible findings of cystoscopy with hydrodistension (HD) and biopsy, as well as clinical implications of cystoscopic information and the concept and use of clinical phenotyping within the context of IC/ BPS were extracted and discussed. IC/BPS is diagnosed based on symptomatic assessment and exclusion of confusable diseases. There is no universal agreement upon the evaluation and diagnostic algorithm of IC/BPS. The majority of the guidelines recommend cystoscopy with HD and biopsy as a diagnostic prerequisite. Various different techniques have been described for cystoscopy with HD. General or epidural anesthesia is more commonly preferred and advocated while assessing endoscopic alterations in patients suspected of having IC/BPS. Cystoscopy with HD and biopsy enables more objective exclusion of confusable diseases. It also provides the basis of the European Society for the Study of Interstitial Cystitis classification. Patients with IC/BPS who demonstrate positive cystoscopic (glomerulations and/or Hunner lesion) and histologic findings have a more severe symptomatology and may benefit from lesion-targeted endoscopic treatments. Clinical phenotyping has been implemented for IC/BPS and may be used for individualized assessment and treatment.


Indications for cystoscopy with hydrodistension and biopsy in IC/BPS
Indications for cystoscopy within the context of IC/BPS evaluation and management exhibit considerable variation. The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) established cystoscopic discovery of glomerulations or Hunner lesions as an unchallenged diagnostic criterion for IC/BPS (7). However, NIDDK criteria were used mainly for the purpose of standardization in scientific studies and the strict application of these criteria would miss a significant proportion of patients who actually have IC/BPS (8). Many experts agreed that the absence of glomerulations or Hunner lesions did not rule out IC/BPS (9).
The ESSIC proposal highlighted the importance of excluding confusable diseases (such as carcinoma in situ) as the cause of symptoms and indicated cystoscopy under anesthesia with hydrodistension (HD) and eventual biopsy as a diagnostic prerequisite (2). Furthermore, cystoscopic and histopathologic findings would enable further documentation and classification of IC/BPS (2). The European Association of Urology (EAU) (10) and the Japanese Urological Association guidelines (11), conjoint expert opinions from East Asia (12), and the Bladder Pain Syndrome Committee of the International Consultation on Incontinence (13) follow the recommendations of the ESSIC. Conversely, the AUA guidelines do not indicate cystoscopy as an integral part of the initial diagnostic evaluation for IC/BPS (1).

Technique of cystoscopy + hydrodistension in IC/BPS
Similar to its indications, the technical protocol of cystoscopy and HD in IC/BPS is subject to considerable variation and lacks consensus. The NIDDK recommended cystoscopy and HD to be performed under anesthesia, at a pressure of 80-100 cm H20, lasting 1-2 minutes, and up to 2 cycles. The presence of Hunner lesions or glomerulations that are diffuse in at least three quadrants with ten glomerulations per quadrant were considered positive findings in favor of IC/BPS (14). The ESSIC and EAU guidelines did not specify technical details about the cystoscopic evaluation for IC/BPS (2,10). According to the AUA guidelines, cystoscopy and HD should be performed under anesthesia, at a pressure of 60-80 cm H20, and be no longer than 10 minutes when the aim is therapeutic (1). The Japanese guidelines recommended lumbar anesthesia at the level of T6 during cystoscopy, with 80 cm H20 pressure, and to stop the infusion when the volume is between 800-1000 mL despite low pressures (11).
Apart from the guideline recommendations, some authors have proposed individual protocols. Turner and Stewart suggested a pressure of 100 cm H20 with a maximum infused volume of 1000 mL, and the distension being maintained for 1 minute.
According to their technique, bladder cycling should not be repeated more than 5 times and cystoscopic assessment should be performed ideally at the initial and last distensions (15).
According to Nordling et al. (16), possible urethral urine leaks around the cystoscope should be blocked digitally. They also suggested that the bladder should be filled with a pressure of 80 cm H20 until the infusion stops dripping, without any specification about the volume limit. Emptying should be started after waiting for 3 minutes with the bladder fully distended. During filling and emptying, which can be repeated one more time, endoscopic assessment is performed. However, they recommend not to reach the maximum capacity during the second cycle to better visualize lesions and optimize tissue sampling (16).
The majority of the published series about IC/BPS stated general or spinal anesthesia as the preferred and recommended type of anesthesia to be applied during cystoscopy with HD. However, some investigators suggested that glomerulations or Hunner lesions could be visualized under local/regional anesthesia (17). Yamada et al. (18) supported the feasibility of epidural anesthesia in an effort to perform additional HDs on the next day following the initial cystoscopy +HD. Aihara et al. (19) used local anesthesia via intravesical administration of lidocaine 10 minutes prior to the start of the infusion, which was terminated when the patient reported intolerable pain or other local symptoms. They reported favorable results in terms of the safety and efficacy of this approach (19).

Cystoscopic findings in IC/BPS
Hunner lesions and glomerulations represent the most characteristic findings that might be encountered during the cystoscopic evaluation for IC/BPS. Hunner lesions were initially called ulcers. However, it is actually an inflammatory lesion that ruptures through the mucosa and submucosa when the bladder is distended. Hence, the suffix 'lesion' would more precisely define its characteristics. Hunner lesions encompass tiny vessels radiating towards a central scar, which is covered by coagulum. When they rupture upon bladder distension, petechial oozing of blood occurs in a waterfall manner ( Figure  1) (2). Hunner lesions are not common, with only around 10-15% of patients with IC/BPS showing consistent cystoscopic signs (19)(20)(21). Narrow band imaging, which helps to distinguish the vascularity of a given bladder mucosal abnormality, has been proposed as an aid to better identify Hunner lesions endoscopically (22). However, more studies are needed to advocate its routine use for this purpose.
Glomerulations are a separate entity and they are defined as small submucosal petechial lesions that become visible after bladder HD (23). They are classified into five grades according to the extent of submucosal bleeding and the presence/ absence of mucosal disruption (16). The term 'glomerulation' was introduced by Walsh who linked these mucosal changes to early stage disease and also highlighted that they were not pathognomonic for IC because other bladder pathologies, such as dyskinesia, might lead to similar alterations in the bladder mucosa (24). Being mainly related to IC/BPS, glomerulations are neither specific nor sensitive enough when used solely for diagnostic purposes. Patients with chronic inflammation of the urothelium, urinary tract stone disease, and benign prostate hyperplasia can exhibit endoscopic signs consistent with glomerulations (25,26). Furthermore, Waxman et al. (27) showed that glomerulations could even be discovered in otherwise healthy women. On the contrary, the proportion of patients with a clinical diagnosis of IC/BPS but with no cystoscopic changes can be in the range of 24-34% (28,29).

Classification of ic/bps according to findings at cystoscopy with hydrodistension and biopsies
According to the ESSIC, cystoscopy and HD with biopsy is an integral part of the diagnostic evaluation for IC/BPS. Cystoscopic positive signs in favor of IC/BPS are glomerulations grade 2-3 or Hunner lesions or both. Infiltration of inflammatory cells and/ or formation of granulation tissue and/or overexpression of mast cells and/or intrafascicular fibrotic changes represent the histopathologic findings that are interpreted in favor of IC/BPS (2). IC/BPS subtypes are defined on the basis of cystoscopic and histopathologic findings (Table 1). If cystoscopy or biopsy are not performed, then the letter X is assigned. Biopsy findings are categorized as follows: normal (A), inconclusive (B), and positive (C). Cystoscopic findings are interpreted as follows: normal (1), glomerulations (2), and Hunner lesion (3). This type of classification could not be possible if only clinical findings were used. Moreover, such a distinction would have implications regarding prognosis and treatment outcome.

Clinical implications and correlations regarding cystoscopy with hydrodistension and biopsy findings in IC/BPS
The clinical relevance of IC/BPS subtypes has long been questioned. However, the information gathered through cystoscopic examinations and histopathological assessments of bladder biopsy samples in IC/BPS offer several advantages regarding optimizing patient management and treatment outcomes. First of all, IC/BPS is essentially a diagnosis of exclusion. Cystoscopy with HD +/-biopsy offers the unique opportunity to exclude some confusable diseases such as carcinoma in-situ and bladder stones in a more reliable manner (2,30).
Moreover, patients with Hunner lesion IC/BPS may benefit from targeted endoscopic interventions. Transurethral resection of Hunner lesions has been associated with symptomatic improvement rates in the range of 90% (31,32). Hunner lesiondirected endoscopic treatment options were further enriched by studies investigating the potential utility of Nd: YAG laser, electrocoagulation, and instillation of triamcinolone (33)(34)(35), all of which reported impressive improvement rates ranging from 70-90%. This therapeutic benefit would not have been possible if these patients were not identified via cystoscopy +/-biopsy. It has been shown that a reliable distinction between Hunner lesion IC/BPS and non-Hunner lesion IC/BPS is not possible via clinical assessment only (36,37). Furthermore, cystoscopy  under local anesthesia can be used to monitor the effect of bladder distension and emptying on pelvic symptoms. Despite the limitation that might be induced by pain and/or discomfort, functional bladder capacity can also be assessed in the same setting (17).  (40).
Finally, cystoscopy is not a morbid procedure, having a fairly low incidence of complications. Relatively few publications have focused on the complications of cystoscopy and HD performed primarily within the context of IC/BPS management. Apart from anecdotal reports of bladder rupture, bladder necrosis, and acute pyelonephritis, the procedure seems to be safe and well tolerated (41,42).

Clinical phenotyping in IC/BPS
IC/BPS is a disorder without a universal agreement upon its etiology, diagnostic algorithm, and management strategy. IC/ BPS may be regarded as a component of a more generalized somatic problem, reflections of which may affect the urinary bladder and other pelvic organs via several proposed mechanisms. The release of mediators such as leukotriene from activated mast cells located close to the neural/perineural structures along the bladder wall is the most widely studied etiopathogenetic explanation for IC/BPS (43).
Diverse clinical phenotypes might be encountered within the context of IC/BPS (44,45). The concurrent existence of IC/BPS with other chronic pain and symptom-based syndromes have been documented (45,46).
The main aim of phenotype mapping for IC/BPS has been to provide more individualized and phenotype-directed clinical assessment and treatment. The urinary symptoms,

Conflict of Interest: No conflict of interest is declared by the authors.
Financial Disclosure: The authors declared that this study received no financial support.