bs_bs_banner

International Journal of Urology (2014) 21 (Suppl 1), 79–82

doi: 10.1111/iju.12325

Original Article

Interstitial cystitis is bladder pain syndrome with Hunner’s lesion Magnus Fall, Yr Logadottir and Ralph Peeker Department of Urology, Sahlgrenska Academy at Gothenburg University and Sahlgrenska University Hospital, Göteborg, Sweden

Abbreviations & Acronyms BPS = bladder pain syndrome IC = interstitial cystitis RNA = ribonucleic acid Correspondence: Magnus Fall M.D., Ph.D., Department of Urology, Sahlgrenska University Hospital, Göteborg S-413 45, Sweden. Email: [email protected] Received 28 August 2013; accepted 24 September 2013.

Abstract: 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

Key words: bladder pain syndrome, chronic cystitis, cystoscopy with hydrodistension, Hunner’s lesion, interstitial cystitis.

Introduction IC was first used by Skene in 1887;1 although, because of a pioneering clinical characterization of the syndrome, the physician who will always be remembered and quoted is Guy Hunner. One hundred years ago, he described a symptom complex of bladder pain associated with a peculiar cystoscopic feature of mucosal lesions, the “elusive ulcer”, later termed Hunner’s ulcer.2 For a number of years, this finding was the hallmark of IC. In 1949, John Hand presented a large series of IC patients. He noted that IC did not comprise just one single entity, but his observation did not attract general attention.3 Later, Messing and Stamey went into more detail about phenotype variation.4 They believed that there might be an early form of the disease, displaying what is called submucosal glomerulations; small, dotted, submucosal bleedings with no similarity to Hunner’s ulcers. They postulated that this entity could eventually progress into the well-known classic disease, whereas Fall et al.5 and Peeker and Fall6 maintained that there are separate phenotypes, related by similar symptoms and a chronic course. The latter statement was based on the fact that a progression from an “early form” to the classic ulcerous form has actually never been reported. Gradually, however, the definition of the generic concept changed, and the scope of IC became wider and more varying while a plethora of treatments were tested, but on which patients? With the object to obtain a standard to be used in scientific studies, the USA National Institute of Diabetes, Digestive and Kidney disorders defined a number of criteria mainly based on exclusions,7 promptly achieving general acceptance. These criteria were also utilized clinically, but were by many found to be too restrictive. Subsequently, IC essentially represented a symptom complex with quite varying contents, an evolution resulting in much confusion in research and even more in the understanding of how to help sufferers to gain symptom relief. Ten years ago, a scientific association was founded, with the object to pay attention to these problems, denominated the European Association for the Study of Interstitial Cystitis. This association, which is now international, the International Association for the Study of Bladder Pain Syndrome, has suggested a standard on how to examine and classify patients with bladder pain, stressed the importance of phenotyping and updated the terminology.8,9 The imperative need of identifying relevant phenotypes of bladder pain states has come into focus, and in this context there is now a renewed interest in the classic type of IC with Hunner’s lesions.

Symptoms There is no doubt that the key to the diagnosis is a careful history with identification of the characteristic symptoms of pain perceived in the urinary bladder, urinary frequency and urgency. © 2014 The Japanese Urological Association

79

M FALL ET AL.

Apart from a general and careful disease-specific history, the degree of symptoms is best illustrated using 2- or 3-day micturition diaries, registering volume and time for each voiding, but also including visual analog scales to describe the degree of pain. These simple instruments can also be used to assess the results of treatment attempts. Pain can be localized to the bladder, or rather in the area that the patient perceives as the bladder, or in the lower abdomen and pelvis. The classic description is imperative urge on bladder filling with increasing suprapubic pain, in many instances very severe, relieved by voiding although soon returning. Subsequent descriptions of sensations are “pressure”, “burning”, “sharp” and “discomfort”. Typically, the pain is felt in, but is not limited to, the supra-pubic region; it can be referred to locations throughout the pelvis, including the urethra, vagina, lower abdomen, lower back, medial aspect of the thigh and the inguinal area in any combination. Consequently, it is not always obvious that the pain is coming from the bladder. Until now, the common understanding has been that various presentations of BPS have quite similar symptoms. That was probably the most important reason to put all forms of BPS into one basket, resulting in the diagnostic confusion of later decades. In disagreement with this opinion, recent observations show that there are differences in symptoms between patients with bladder lesions compared with those without. The characteristics of pain were found to correlate to the cystoscopic findings,10 and various components in the voiding diary were found to differ, suggesting that a voiding score could actually predict the cystoscopic appearance of the bladder.11 Although bladder pain and urinary frequency might be the only or major complaints in some individuals, others have a broader spectrum of problems, including associations of BPS/IC to allergy, fibromyalgia, vulvodynia, Sjögren syndrome, chronic fatigue syndrome, anxiety disorders and depression. Such associations should be acknowledged in the patient’s history; they might be of importance in the identification of various phenotypes.

Cystoscopy and pelvic examination Cystoscopy under anesthesia is the cornerstone for the investigation of BPS/IC patients to visualize lesions characteristic of BPS/IC, with special attention to the presence or absence of Hunner’s lesions. Adequate distention is required to identify such lesions with sufficient certainty. Local anesthetic cystoscopy is still a useful first step to examine the bladder and urethral mucosa, urethral caliber, to identify suspect lesions and determine the degree of local tenderness of the bladder and/or urethra. Abnormal tenderness or heightened sensation of the external and internal genitalia, and the various components of the pelvic floor are also noted, including any trigger points. Such physical signs are important for diagnostic completeness and the design of a rational treatment program. The BPS/IC patient can tolerate filling with only a very limited volume in their unanesthetized bladder, irrespective of the true bladder capacity during anesthesia. Other possible causes for lower urinary tract pain, such as tumor, stone, inflammation or mucosal metaplasias, can be noted or excluded.9 The presence of submucosal petechial bleedings, so called glomerulations, after decompression of the previously distended bladder, has 80

Fig. 1 Lesion in classic IC (European Association for the Study of Interstitial Cystitis type 3C), viewed though a resectoscope during bladder distension: small vessels radiating towards discrete central scar, with superficial rupture and water-fall like bleeding.

until recently been regarded as one of the endoscopic hallmarks of the disease.3,8 Current data is however casting doubt on the diagnostic usefulness of this finding.12,13 It is worth laying stress on the fact that Hunner’s lesions can only be fully identified and characterized with cystoscopy under anesthesia. The typical lesion is a circumscribed, reddened mucosal area with small vessels radiating towards a central scar, with a fibrin deposit or coagulum attached to this area. It is not a true ulcer, but rather a very vulnerable, inflamed area. On further bladder distension this site ruptures (Fig. 1), with petechial hemorrhage from the lesion and the mucosal margins in a waterfall manner, and with a central vulnus provoked by bladder wall stretch. The denomination Hunner’s ulcer is therefore incorrect, Hunner’s lesion is the preferred term.9 A quite characteristic finding at the second filling of the bladder in a patient with this classic type of lesion is a varying degree of edema, sometimes with peripheral extension.5,9 Diagnostic hydrodistension should be carried out in a standard manner at a pressure of 80 cmH2O above the level of the patient’s bladder. Irrigating fluid is allowed to run into the bladder until it stops spontaneously at capacity, as observed when checking the dripping chamber of the fluid reservoir. This volume is then held for 2–3 min with any leakage around the cystoscope sheath controlled by urethral compression. The volume and the degree of bleeding into the bladder fluid are noted when evacuating the bladder. The maximum bladder capacity is often reduced in the classic type of IC, whereas it is normal or only slightly reduced in the non-Hunner BPS.6 The bladder is refilled to approximately 20–50% of capacity, and again inspected for lesions and hemorrhages, which will not be conspicuous until the bladder is filled for a second time. Over the years, controversy has developed as to the prevalence and even the actual existence of the Hunner’s lesion, and some urologists maintain that they are rare, or do not exist, and the fact that they rarely detect them confirms this false impression. The distribution varies from 5 to 50% of cases with BPS in various populations, centers and series. Fortunately, the © 2014 The Japanese Urological Association

Hunner lesion is IC

awareness of the indispensability of cystoscopy in BPS/IC diagnostics is increasing. However, detection is certainly a matter of attention and training. Supplementary techniques might be helpful to increase the detection rate, like the narrow band method.14

Histopathology The primary purpose of obtaining bladder biopsies in BPS/IC is to exclude other causes of bladder pain,9 principally serious diseases, such as carcinoma in situ. Histopathological examination is also of value in diagnosing BPS/IC. Although the histopathological features are not distinctive in non-ulcer disease, there are microscopic findings pathognomonic for classic IC. These include urothelial vacuolization and detachment, mucosal infiltrates of lymphocytes, plasma cells, neutrophil and eosinophil granulocytes, as well as increase of mast cell numbers in all compartments of the bladder wall.15–18 Granulation tissue is one further feature of the classic disease, quite likely as a result of repeated trauma by bladder filling and stretch of the areas of inflammatory involvement.18 In an analysis of pathological findings in more than 200 USA patients with IC, three morphology clusters were identified, corresponding to unique pathological groupings. The largest group comprised 90% of patients with no consistent pathological features, that group plausibly being synonymous with the so called non-ulcer category according to previous terminology.18 A small second group showed multiple signs of parenchymal damage, including several inflammatory features, whereas the third group was characterized by complete denudation of the urothelium and variable edema. This categorization correlated with symptom complex and symptom severity, indicating a role for histopathology in the predictive modeling of BPS/IC.19 Morphological methods continue to evolve using immunohistochemistry, polymerase chain reaction in situ, and various immunoblotting and RNA expression array techniques. One example is the application of tryptase staining for mast cells, currently the technique of choice.17,20 By development of laboratory techniques, the precision of the diagnosis might be improved in the future. It is interesting to further explore the role of the various components of the cell infiltrate, although as yet poorly characterized. For example, lymphocytes have one role: studies suggest that T- and B cells are associated with various clinical features of IC, and moreover there are differences in lymphocyte populations in classic versus non-ulcer disease.21,22 Macrophages have another role,23,24 like possibly in a massive production of nitric oxide seen in the Hunner type of disease. Again, special interest has been devoted to the mast cell, supposed to be a major player in this disease complex, involving the diagnosis, development of symptoms and relationship to detrusor fibrosis, to give some examples.15,17,25,26 Mast cells can be activated by a variety of agents, leading to release of a number of distinct inflammatory mediators, with or without degranulation. How these differential mast cell responses are controlled is still unresolved.27 Investigating the cause and effect in different bladder wall cellular responses is required to be able to show the nature of various BPS/IC phenotypes, particularly so in the Hunner type of disease with all its characteristic histopathological features. © 2014 The Japanese Urological Association

Role of markers Characterization of a predictive urinary or serum biomarker for the diagnosis and likely treatment responsiveness of patients with possible BPS/IC would be a tremendous advance. The heterogeneity of the syndrome makes it unlikely that a single biomarker could cover the entire spectrum, though. The most promising candidate is antiproliferative factor, a component of urine that inhibits urothelial cell proliferation, which appears in a higher concentration in BPS/IC patients compared with controls.28 However, there is insufficient evidence to support antiproliferative factor as a generally useful diagnostic tool. The many other candidates tested remain confined to the research field. A further possibility arises from the observation that the formation of urinary nitric oxide is increased in patients with the classic Hunner lesional form of IC.29 This production might occur in different tissue compartments including the urothelium23 and in infiltrating inflammatory cells present in IC.24 Although, at this stage, biomarkers have a limited role in routine diagnosis of BPS/IC, they hold promises for the future.

Genetics The etiology of BPS/IC is poorly understood and there have been suggestions that genetic mechanisms could play a role. Data are conflicting, though. Examples of intriguing recent observations are that gene upregulation of sediment cells in IC patients has been described.30 There are further suggestions that genome-based expression profiling can be used in the diagnosis of the Hunner type of disease in clinical practice.31 This represents another fascinating field for future research.

Conclusion 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. The classic Hunner disease (BPS type 3C) is a specific and well-defined disease, and fulfils the requirements for the denomination “interstitial cystitis”: there are histological signs of a marked inflammation in the bladder submucosa and musculature (the bladder interstitium). Evidence is accumulating on unique and outstanding features of this entity. With satisfaction, we note that today there is acceptance of this entity to be evaluated separately in clinical studies, as treatment requirements differ importantly between this and other phenotypes. The classic Hunner type entity is what from the beginning was meant by the term and disease, IC. We have now gone around the circle and come back to the particular condition originally understood by the name, IC.

Acknowledgment This work was supported by The University of Gothenburg ALF project n: o 7582.

Conflict of interest None declared. 81

bs_bs_banner

M FALL ET AL.

References 1 Skene AJC. Diseases of Bladder and Urethra in Women. Wm Wood, New York, 1887; 167 p. 2 Hunner GL. Elusive ulcer of the bladder: further notes on a rare type of bladder ulcer with report of 25 cases. Am. J. Obstet. 1918; 78: 374–95. 3 Hand JR. Interstitial cystitis: report of 223 cases (204 women and 19 men). J. Urol. 1949; 61: 291–310. 4 Messing EM, Stamey TA. Interstitial cystitis: early diagnosis, pathology and treatment. Urology 1978; 12: 381–92. 5 Fall M, Johansson SL, Aldenborg F. Chronic interstitial cystitis: a heterogeneous syndrome. J. Urol. 1987; 137: 35–8. 6 Peeker R, Fall M. Towards a precise definition of interstitial cystitis: further evidence of differences in classic and nonulcer disease. J. Urol. 2002; 167: 2470–2. 7 Wein A, Hanno P, Gillenwater J. Interstitial cystitis: an introduction to the problem. In: Hanno PM, Staskin DR, Krane RJ, Wein AJ (eds). Intersititial Cystitis. Springer-Verlag, London, 1990; 13–15. 8 Nordling J, Anjum F, Bade J et al. Primary evaluation of patients suspected of having interstitial cystitis (IC). Eur. Urol. 2004; 45: 662–9. 9 van de Merwe JP, Nordling J, Bouchelouche P et al. Diagnostic criteria, classification, and nomenclature for painful bladder syndrome/interstitial cystitis: an ESSIC proposal. Eur. Urol. 2008; 53: 60–7. 10 Lamale L, Lutgendorf S, Hoffman A, Kreder K. Symptoms and cystoscopic findings in patients with untreated interstitial cystitis. Urology 2006; 67: 242–5. 11 Boudry G, Labat J, Normand L, Manunta A, Bensalah K, Rigaud J. Validation of voiding diary for stratification of bladder pain syndrome according to the presence/absence of cystoscopic abnormalities: a two-centre prospective study. BJU Int. 2013; 112: E164–8. 12 Waxman J, Sulak P, Kuehl T. Cystoscopic findings consistent with interstitial cystitis in normal women undergoing tubal ligation. J. Urol. 1998; 160: 1663–7. 13 Richter B, Hesse U, Hansen A, Horn T, Mortensen S, Nordling J. Bladder pain syndrome/interstitial cystitis in a Danish population: a study using the 2008 criteria of the European Society for the Study of Interstitial Cystitis. BJU Int. 2010; 105: 660–7. 14 Ueda T, Nakagawa M, Okamura M, Tanoue H, Yoshida H, Yoshimura N. New cystoscopic diagnosis for interstitial cystitis/painful bladder syndrome using narrow-band imaging system. Int. J. Urol. 2008; 15: 1039–43. 15 Aldenborg F, Fall M, Enerbäck L. Proliferation and transepithelial migration of mucosal mast cells in interstitial cystitis. Immunology 1986; 58: 411–6. 16 Fall M, Johansson SL, Vahlne A. A clinicopathological and virological study of interstitial cystitis. J. Urol. 1985; 133: 771–3.

17 Peeker R, Fall M, Enerbäck L, Aldenborg F. Recruitment, distribution and phenotypes of mast cells in interstitial cystitis. J. Urol. 2000; 163: 1009–15. 18 Johansson SL, Fall M. Clinical features and spectrum of light microscopic changes in interstitial cystitis. J. Urol. 1990; 143: 1118–24. 19 Leiby B, Landis J, Propert K, Tomaszewski J, Group ICDBS. Discovery of morphological subgroups that correlate with severity of symptoms in interstitial cystitis: a proposed biopsy classification system. J. Urol. 2007; 177: 142–8. 20 Larsen M, Mortensen S, Nordling J, Horn T. Quantifying mast cells in bladder pain syndrome by immunohistochemical analysis. BJU Int. 2008; 102: 204–7. 21 Erickson DR, Belchis DA, Dabbs DJ. Inflammatory cell types and clinical features of interstitial cystitis. J. Urol. 1997; 158: 790–3. 22 Harrington DS, Fall M, Johansson SL. Interstitial cystitis: bladder mucosa lymphocyte immunophenotyping and peripheral blood flow cytometry analysis. J. Urol. 1990; 144: 868–71. 23 Koskela L, Thiel T, Ehren I, De Verdier P, Wiklund N. Localization and expression of inducible nitric oxide synthase in biopsies from patients with interstitial cystitis. J. Urol. 2008; 180: 737–41. 24 Logadottir Y, Hallsberg L, Fall M, Peeker R. Bladder Pain Syndrome/Interstitial Cystitis ESSIC Type 3C: high expression of inducible nitric oxide synthase in inflammatory cells. Scand. J. Urol. Nephrol. 2013; 47: 52–6. 25 Larsen S, Thompson SA, Hald T et al. Mast cells in interstitial cystitis. Br. J. Urol. 1982; 54: 283–6. 26 Sant G, Kempuraj D, Marchand J, Theoharides T. The mast cell in interstitial cystitis: role in pathophysiology and pathogenesis. Urology 2007; 69 (4 Suppl): 34–40. 27 Theoharides T, Kempuraj D, Tagen M, Conti P, Kalogeromitros D. Differential release of mast cell mediators and the pathogenesis of inflammation. Immunol. Rev. 2007; 217: 65–78. 28 Kim J, Keay S, Freeman M. Heparin-binding epidermal growth factor-like growth factor functionally antagonizes interstitial cystitis antiproliferative factor via mitogen-activated protein kinase pathway activation. BJU Int. 2009; 103: 541–6. 29 Logadottir Y, Ehren I, Fall M, Wiklund NP, Peeker R. Intravesical Nitric Oxide Production Discriminates between classic and nonulcer interstitial cystitis. J. Urol. 2004; 171: 1148–51. 30 Blalock E, Korrect G, Stromberg A, Erickson D. Gene expression analysis of urine sediment: evaluation for potential noninvasive markers of interstitial cystitis/bladder pain syndrome. J. Urol. 2012; 187: 725–32. 31 Tseng L, Chen I, Wang C, Lin Y, Lloyd L, Lee C. Genome-based expression profiling study of Hunner’s ulcer type interstitial cystitis: an array of 40-gene model. Int. Urogynecol. J. 2010; 21: 911–8.

Editorial Comment Editorial Comment from Dr Hanno to Interstitial cystitis is bladder pain syndrome with Hunner’s lesion In 2008, the European Society for the Study of Interstitial Cystitis (ESSIC) group published a paper defining bladder pain syndrome as follows: Bladder Pain Syndrome (BPS), which would be diagnosed on the basis of chronic pelvic pain, pressure or discomfort perceived to be related to the urinary bladder accompanied by at least one other urinary symptom like persistent urge to void or urinary frequency. Confusable diseases as the cause of the symptoms must be excluded. Further documentation and classification of BPS might be performed according to findings at cystoscopy with hydrodistention and morphological findings in bladder biopsies. The presence of other organ symptoms as well as cognitive, behavioural, emotional and sexual symptoms 82

should be addressed.1 A very similar definition was a central part of the guideline of the American Urological Association published 3 years later.2 Because the diagnosis of BPS is based solely on symptoms, it became a diagnosis of exclusion. Many diseases might cause bladder pain, and an evaluation was suggested to define such confusable diseases and how they are excluded. This excellent article by Fall, Logadottir and Peeker asks us to rethink what BPS with Hunner’s lesions really is and how it might be referred to. If BPS is a syndrome, then specific pathological disorders that can be readily identified should be distinct and apart from the syndrome, which is by definition, a diagnosis based solely on symptoms and one of exclusion. © 2014 The Japanese Urological Association

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...
189KB Sizes 2 Downloads 3 Views