Hunner lesion disease differs in diagnosis, treatment and outcome from bladder pain syndrome: an ESSIC working group report.

Objectives: There is confusion about the terms of bladder pain syndrome (BPS) and Interstitial Cystitis (IC). The European Society for the Study of IC (ESSIC) classified these according to objective findings [9]. One phenotype, Hunner lesion disease (HLD or ESSIC 3C) differs markedly from other presentations. Therefore, the question was raised as to whether this is a separate condition or BPS subtype.Methods: An evaluation was made to explore if HLD differs from other BPS presentations regarding symptomatology, physical examination findings, laboratory tests, endoscopy, histopathology, natural history, epidemiology, prognosis and treatment outcomes.Results: Cystoscopy is the method of choice to identify Hunner lesions, histopathology the method to confirm it. You cannot distinguish between main forms of BPS by means of symptoms, physical examination or laboratory tests. Epidemiologic data are incomplete. HLD seems relatively uncommon, although more frequent in older patients than non-HLD. No indication has been presented of BPS and HLD as a continuum of conditions, one developing into the other.Conclusions: A paradigm shift in the understanding of BPS/IC is urgent. A highly topical issue is to separate HLD and BPS: treatment results and prognoses differ substantially. Since historically, IC was tantamount to Hunner lesions and interstitial inflammation in the bladder wall, still, a valid definition, the term IC should preferably be reserved for HLD patients. BPS is a symptom syndrome without specific objective findings and should be used for other patients fulfilling the ESSIC definitions.

Hunner lesion versus non-Hunner lesion interstitial cystitis/bladder pain syndrome.

BACKGROUND: Global consensus on the standardization of terminology for interstitial cystitis/bladder pain syndrome is lacking and is in the formative stages. The Workshop on Hunner lesion versus non-Hunner lesion at the 2018 International Consultation on Interstitial Cystitis Japan discussed prevalence, performance and outcome of endoscopy, the role of histopathology, and markers. METHODS: A panel of experts reviewed the literature regarding Hunner lesion vs. non-Hunner lesion interstitial cystitis/bladder pain syndrome. RESULTS: The prevalence of Hunner lesion has been reported to be 5-57%. Older age and smaller anatomic bladder capacity were associated with Hunner lesions. Cystoscopy using local anesthesia is not adequate in diagnosing interstitial cystitis but is needed to rule out confusable diseases. Cystoscopy with hydrodistention and redistention of the bladder is considered standard. A Hunner lesion is visualized as a quite typical inflammatory reaction: a reddened mucosal area with small vessels radiating towards a central scar, splitting at distension, usually associated with a waterfall bleeding pattern. Biopsies from the inflamed area show inflammatory infiltrates, granulation tissue, detrusor mastocytosis, and fibrin deposits. Ablation of Hunner lesions includes transurethral resection of lesions, fulguration, laser ablation, and cortical steroid injections. Mast cell density is a somewhat controversial matter, described differently in different studies: marked increase in Hunner lesion vs. non-Hunner lesion in the majority of studies, no difference in a few. Nitric oxide appears to be a definitive marker in distinguishing Hunner lesion vs. non-Hunner lesion disease. Macrophage migration inhibitory factor is elevated in Hunner lesion patients. Increased level of urinary proinflammatory genes expression has also been found in Hunner lesion subjects. CONCLUSIONS: Hunner lesion patients are clinically and pathologically distinct from non-Hunner lesion bladder pain syndrome patients.

Elevated Urine Levels of Macrophage Migration Inhibitory Factor in Inflammatory Bladder Conditions: A Potential Biomarker for a Subgroup of Interstitial Cystitis/Bladder Pain Syndrome Patients.

OBJECTIVE: To investigate whether urinary levels of macrophage migration inhibitory factor (MIF) are elevated in interstitial cystitis/bladder pain syndrome (IC/BPS) patients with Hunner lesions and also whether urine MIF is elevated in other forms of inflammatory cystitis. METHODS: Urine samples were assayed for MIF by enzyme-linked immunosorbent assay. Urine samples from 3 female groups were examined: IC/BPS patients without (N = 55) and with Hunner lesions (N = 43), and non-IC/BPS patients (N = 100; control group; no history of IC/BPS; cancer or recent bacterial cystitis). Urine samples from 3 male groups were examined: patients with bacterial cystitis (N = 50), radiation cystitis (N = 18) and noncystitis patients (N = 119; control group; negative for bacterial cystitis). RESULTS: Urine MIF (mean MIF pg/mL ± standard error of the mean) was increased in female IC/BPS patients with Hunner lesions (2159 ± 435.3) compared with IC/BPS patients without Hunner lesions (460 ± 114.5) or non-IC/BPS patients (414 ± 47.6). Receiver operating curve analyses showed that urine MIF levels discriminated between the 2 IC groups (area under the curve = 72%; confidence interval 61%-82%). Male patients with bacterial and radiation cystitis had elevated urine MIF levels (2839 ± 757.1 and 4404 ± 1548.1, respectively) compared with noncystitis patients (681 ± 75.2). CONCLUSION: Urine MIF is elevated in IC/BPS patients with Hunner lesions and also in patients with other bladder inflammatory and painful conditions. MIF may also serve as a noninvasive biomarker to select IC/BPS patients more accurately for endoscopic evaluation and possible anti-inflammatory treatment.

The extracellular matrix-degrading protein ADAMTS5 is expressed in the nuclei of urothelial cells in healthy rats.

OBJECTIVE: The aim of this study was to investigate whether protein expression of the extracellular matrix-degrading protease ADAMTS5 can be demonstrated in the urinary bladder of healthy rats, and, if so, to determine the localization of this enzyme. MATERIALS AND METHODS: The experiments were conducted with eight inbred male Sprague-Dawley rats. Immunohistochemistry was used to investigate the expression of ADAMTS5 in the urinary bladder. Negative controls were established by either excluding the primary antibody or applying the antibody after it had been preabsorbed with its immunogenic peptide. Confocal microscopy was used to visualize the distribution of ADAMTS5 in the urinary bladder tissue. RESULTS: Immunoreactivity for ADAMTS5 was demonstrated in the urothelium and in the detrusor. This expression was localized not only in the cytoplasm, but also in the nuclei. Confocal microscopy corroborated these findings. CONCLUSION: Expression of ADAMTS5 was demonstrated in the cytoplasm as well as in the nuclei of the urothelium and detrusor cells, suggesting that it may play a role at the transcriptional level.

High revision rate following artificial urethral sphincter implantation.

OBJECTIVE: In severe cases of stress urinary incontinence (SUI), with sphincter dysfunction, the artificial urinary sphincter AMS 800™ may be the last solution. The purpose of this study was to evaluate the outcome of surgical intervention for SUI with the AMS 800 in patients who were treated at Sahlgrenska University Hospital, Gothenburg. The primary aim of the study was to determine the complications related to the operation. MATERIAL AND METHODS: A retrospective follow-up was done by reviewing medical records. The material comprised 97 men, who underwent their first AMS 800 implantation between May 1997 and June 2010 at Sahlgrenska University Hospital. RESULTS: The revision rate was 28%, including an infection rate of 3% and an erosion rate of 7%. The mean follow-up for revised patients was 3 years. The median time until revision was 1 year. Seventy-five per cent of all patients were satisfied with the operation at 6 months' follow-up. Radical prostatectomy was the reason behind incontinence in 84% of patients in this series. CONCLUSION: The results clearly demonstrate a need for revision procedures in a considerable proportion of patients implanted with an AMS 800 device. Patient satisfaction was high, but although this operation has extremely low mortality it has its complications and the system will need to be replaced in time.

Inflammation characteristics in bladder pain syndrome ESSIC type 3C/classic interstitial cystitis.

OBJECTIVES: Interstitial cystitis is regarded as a heterogenous syndrome with two distinguishable forms: the non-ulcer and the classic form of interstitial cystitis, the latter with Hunner's lesions; or bladder pain syndrome type 3C and non-Hunner bladder pain syndrome, respectively. METHODS: A cohort of 379 patients diagnosed with interstitial cystitis was studied. Nitric oxide release from the bladder was measured using a chemiluminescence nitric oxide analyzer. Bladder biopsies from the patients and healthy controls were analyzed by routine histopathological examination. Biopsies from a subset of patients and controls were also analyzed by immunohistochemistry and cytokine gene expression by real-time polymerase chain reaction. RESULTS: Patients with bladder pain syndrome type 3C/classic interstitial cystitis had considerably higher levels of nitric oxide as compared with non-Hunner bladder pain syndrome/non-ulcer interstitial cystitis patients and healthy individuals, and showed histologically a chronic inflammation in the bladder mucosa, with abundant mast cell infiltration in all layers of the bladder wall. No inflammation was noted in non-Hunner bladder pain syndrome/non-ulcer interstitial cystitis patients. The isoenzymes inducible nitric oxide synthase, the catalyst in the nitric oxide production, was strongly expressed in the inflammatory cells in the bladder mucosa of bladder pain syndrome type 3C/classic interstitial cystitis patients. In addition, the expression of the pro-inflammatory cytokines interleukin-6 and interleukin-17A messenger ribonucleic acid, and of anti-inflammatory interleukin-10 messenger ribonucleic acid showed significantly increased levels in bladder pain syndrome type 3C/classic interstitial cystitis compared with healthy controls. CONCLUSION: Bladder pain syndrome type 3C/classic interstitial cystitis is a distinct inflammatory disease and in many aspects shares features of inflammatory autoimmune diseases. These findings could open up novel research avenues with expectations for new targets for pharmacological treatment.

Interstitial cystitis is bladder pain syndrome with Hunner's lesion.

The contents and understanding of the term, interstitial cystitis, have undergone major changes during the past 100 years, moving from a chronic, true inflammatory bladder disorder to an extensive syndrome with lower urinary tract pain. Comments on this development are presented. From examples in the literature, some important features of classic interstitial cystitis are outlined. The more inclusive attitude of later decades has drawn desirable attention to the entire spectrum of disorders resulting in bladder pain. The wish to include all of them into one handy entity has unfortunately resulted in much scientific and clinical confusion, though. It is noted that originally interstitial cystitis represented the Hunner type of disease. Today, there is agreement that the classic type of interstitial cystitis with Hunner's lesions, bladder pain syndrome type 3C according to current terminology, stands out as a well-defined phenotype; it has to evaluated separately in clinical studies and practice, as treatment requirements differ importantly between this and other phenotypes.

Cytokine expression in patients with bladder pain syndrome/interstitial cystitis ESSIC type 3C.

PURPOSE: Bladder wall nitric oxide production in patients with bladder pain syndrome type 3C is increased compared to undetectable nitric oxide in patients with nonHunner bladder pain syndrome and healthy controls. However, the underlying mechanism/s of the increased nitric oxide production is largely unknown. We compared mRNA expression of a select group of cytokines in patients with bladder pain syndrome/interstitial cystitis type 3C and in pain-free controls. MATERIALS AND METHODS: Cold cup biopsies from 7 patients with bladder pain syndrome type 3C and 6 healthy subjects were analyzed. mRNA expression of IL-4, 6, 10 and 17A, iNOS, TNF-α, TGF-ß and IFN-γ was estimated by real-time polymerase chain reaction. IL-17 protein expression was determined by immunohistochemistry. Mast cells were labeled with tryptase to evaluate cell appearance and count. RESULTS: IL-6, 10 and 17A, and iNOS mRNA levels as well as the number of mast cells infiltrating the bladder mucosa were significantly increased in patients with bladder pain syndrome type 3C compared to healthy controls. TNF-α, TGF-ß and IFN-γ mRNA levels were similar in patients and controls. IL-17A expression at the protein level was up-regulated and localized to inflammatory cells and urothelium in patients with bladder pain syndrome type 3C. CONCLUSIONS: Patients with bladder pain syndrome/interstitial cystitis had increased mRNA levels of IL-17A, 10 and 6, and iNOS. IL-17A might be important in the inflammatory process. To our knowledge the increase in IL-17A is a novel finding that may have new treatment implications.

Methods and incentives for the early diagnosis of bladder pain syndrome/interstitial cystitis.

INTRODUCTION: The concept of interstitial cystitis (IC) has changed dramatically during the last decades, eventually representing a symptom complex with varying contents. To include all patients with bladder pain, the umbrella term 'bladder pain syndrome' (BPS) has been suggested, incorporating the classic presentation of IC as a separate phenotype. This change of concepts has not been uncontroversial. Bladder pain syndrome often has a profound effect on the patients' quality of life. Generally, recognition of this problem complex is hampered by insufficient familiarity in the medical community. The correct diagnosis is often delayed by several years and may be preceded by multiple medical consultations and treatment attempts. There is no doubt that an early and correct diagnosis is of great significance for the patient. AREAS COVERED: In this article, a critical review of methods and means to approach the diagnosis is presented including some notes of current controversies. EXPERT OPINION: The key to an early diagnosis is symptom recognition. We are dealing with a heterogeneous concept including various phenotypes. The successful treatment requires understanding and expedient use of objective means, such as cystoscopy, biopsy and input from the multidisciplinary team. In the literature, limited evidence exists for the management of BPS/IC, due to heterogeneity in methodology and description of the syndrome(s). A more consequent use of available methods is desirable. For the immediate future, better understanding of the aetiology, pathogenesis and presentation of various BPS/IC phenotypes is indispensable.

Urovaginal fistula formation after gynaecological and obstetric surgical procedures: clinical experiences in a Scandinavian series.

OBJECTIVE: The aim of this retrospective study was to review what kinds of surgical procedures are most frequently complicated by urovaginal fistulae, to find out how they were diagnosed and managed, and to study the outcome after surgical reconstruction. MATERIAL AND METHODS: Nineteen women who underwent fistula repair at Sahlgrenska University Hospital between 2003 and 2009 were retrospectively studied by reviewing the medical records. RESULTS: For 17 of the 19 patients hysterectomy was the causative procedure. Fourteen patients developed vesicovaginal and five developed ureterovaginal fistula. Urethrocystoscopy was sufficient for the diagnosis in nearly 50% of the patients and when combined with methylene blue instillation 90% of all fistulae were found. Several patients sought medical advice due to vaginal leakage following gynaecological surgery without the doctor suspecting a fistula, and for these patients the diagnosis was delayed. Eighteen patients were operated on with an abdominal approach and one with a vaginal approach, in all cases a minimum of 3 months after primary surgery. The reconstruction technique included the interposition of vascularized tissue. None of the patients reported leakage or relapse at follow-up after fistula repair. CONCLUSIONS: Hysterectomy was the most common cause behind the formation of urovaginal fistulae. Misinterpretation of symptoms after gynaecological surgery was common even in cases where the symptoms were indicative of a urovaginal fistula. Delayed fistula repair after a minimum of 3 months, via the abdominal route and with the interposition of vascularized tissue, yielded an excellent final outcome.

Bladder pain syndrome/interstitial cystitis ESSIC type 3C: high expression of inducible nitric oxide synthase in inflammatory cells.

OBJECTIVE: Bladder pain syndrome/interstitial cystitis (BPS/IC) includes a heterogeneous collection of underlying pathological conditions. Compared to the classic IC with a Hunner lesion, now denominated ESSIC type 3C, the non-Hunner type of BPS/IC appears different in a number of respects. In a previous study, measuring luminal nitric oxide (NO) in the bladder of patients with BPS/IC, it was reported that all patients with ESSIC type 3C had high levels of NO. The aim of the present study was to investigate the source of inducible nitric oxide synthase (iNOS) and thereby the cellular origin of NO production via iNOS. MATERIAL AND METHODS: Immunohistochemistry, with two different anti-iNOS antibodies, was used to study 10 patients with BPS/IC ESSIC type 3C who expressed high levels of intraluminal NO. These results were compared with four patients with non-Hunner BPS/IC. To substantiate further the involvement of iNOS in this condition, the protein expression of nitrotyrosine, a marker for iNOS activation, was also assessed. RESULTS: On routine histopathology, the tissues of type 3C patients exhibited inflammatory infiltrates of varying intensity. Strong immunoreactivity for both iNOS and nitrotyrosine was noted within the urothelium but also within the inflammatory infiltrates in the lamina propria of these subjects. CONCLUSIONS: The findings of a clearly detectable protein expression of iNOS in both the urothelium and the inflammatory infiltrates in bladder biopsies from patients with BPS/IC ESSIC type 3C suggest that the production of NO, in this entity, may occur in different tissue compartments.

Clinical characteristics differ considerably between phenotypes of bladder pain syndrome/interstitial cystitis.

OBJECTIVE: Bladder pain syndrome/interstitial cystitis (BPS/IC) is one of the most bothersome conditions in urological practice. This syndrome includes a heterogeneous collection of underlying pathological conditions. Compared to the classic IC with a Hunner lesion, now denominated European Society for the Study of Interstitial Cystitis (ESSIC) type 3C, the non-Hunner type of BPS/IC appears different concerning demographic, endoscopic and histological findings, as well as the response to all forms of treatment. The objective of this study was to determine whether there are additional dissimilarities in clinical presentation between the main phenotypes of BPS/IC. MATERIAL AND METHODS: In total, 393 BPS/IC patients (210 type 3C and 183 non-Hunner), diagnosed according to National Institute of Diabetes and Digestive and Kidney Diseases and ESSIC criteria, were studied by surveying the clinical records including micturition diaries. RESULTS: In this clinical material, BPS/IC ESSIC type 3C accounted for 55% of cases. Patients with non-Hunner disease were on average 20 years younger at the time of diagnosis. Furthermore, there was a marked and significant difference in bladder capacity under general anaesthesia (p < 0.0001). CONCLUSIONS: The findings in the present series, together with previously published reports by this group and by others, confirm the striking differences between the main forms of BPS/IC and underline the indispensability of adequate subtyping in clinical studies.

Global concepts of bladder pain syndrome (interstitial cystitis).

BACKGROUND: Bladder pain syndrome (BPS), commonly referred to as "interstitial cystitis", is no longer considered a rare disorder. It may affect up to 2.7% of the adult female population (Ueda et al. in Int J Urol 10:1-70, 2003) with up to 20% of cases occurring in men. METHODS: The last two decades have seen a worldwide effort to try to standardize its nomenclature, definition, diagnosis, and treatment algorithm. The literature has been reviewed. RESULTS: In this article, we will detail current terminology, diagnostic approaches and treatment. Standard therapies will be discussed, and a section that concentrates on the management of the subset of patients with a Hunner's lesion will be highlighted. CONCLUSIONS: BPS is today viewed through a new paradigm. It is no longer considered primarily a bladder disease, but rather one of a number of chronic pain syndromes that is distinguished by being manifest through bladder-related symptoms. A distinct subgroup of patients with Hunner's lesion has specific characteristics, and successful treatment of this subgroup is available.