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Current Bladder Dysfunction Reports ISSN 1931-7212 Curr Bladder Dysfunct RepDOI 10.1007/s11884-014-0273-4

Classic Interstitial Cystitis: Unrelated toBPS

Magnus Fall & Ralph Peeker

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PELVIC PAIN (C PAYNE AND J POTTS, SECTION EDITORS)

Classic Interstitial Cystitis: Unrelated to BPS

Magnus Fall & Ralph Peeker

# Springer Science+Business Media New York 2015

Abstract When first recognized, more than one hundredyears ago, the term interstitial cystitis (IC) was reserved forsubjects with a special type of deep inflammation of the blad-der wall. Later, the scope of IC widened, including all kinds ofbladder pain syndromes (BPS), giving rise to a lot of confu-sion and difficulties in research as well as in clinical practice.Herein, recent progress in the understanding of the BPS/ICcomplex will be discussed, emphasizing the fact that the clas-sic Hunner disease (BPS type 3C according to the EuropeanSociety for the Study of Interstitial Cystitis (ESSIC) classifi-cation) is a well-defined condition that fulfills the require-ments of the denomination interstitial cystitis. The paper willalso discuss recent research on diagnostics, markers, genetics,and various types of remedies for classic IC. For the benefit ofour patients, in BPS/IC, it is time for a final separation of theconcepts BPS and IC. Classic IC is a well-defined entity withmultiple unique characteristics, those characteristics having apotential for development of a specific rational, pharmacolog-ical, and surgical treatment algorithm if further investigated.BPS, on the other hand, seems to include a heterogenic com-position of conditions calling for broad attempts to be moreclosely explored.

Keywords Bladder pain syndrome . Interstitial cystitis .

Classification . Phenotype definitions

Introduction

More than one hundred years ago, in patients with a chronicbladder disorder, a condition was found characterized by adeep inflammatory involvement of the bladder wall anddenominated interstitial cystitis (IC) [1]. Later, this conditionwas closely described by Dr. Guy Hunner as a symptom com-plex of bladder pain, related to bladder filling, and a peculiarbut characteristic cystoscopic appearance with rather typicalmucosal lesions [2], the so-called elusive ulcers or laterHunner’s ulcers. For a long time, these findings were tanta-mount to the term IC, and urologists of earlier time were quitefamiliar with this classic form; in fact, that was IC, no less, nomore. Later, Hand [3] noted other features of the classic pic-ture that were present in painful bladders, but at this stage, hisobservations did not have much of impact and did not influ-ence nomenclature. There was a gradual change, however.Thirty years later, when Messing and Stamey [4] looked atsubtypes, they acknowledged a diversity of concepts andthought that there might be an early form of the disease with-out Hunner’s lesions but with the so-called glomerulations,small, dotted submucosal bleedings occurring after bladderdistension. They postulated that this entity could eventuallyprogress into the well-known classic disease. We main-tained that there exist separate phenotypes, related by sim-ilar symptoms and a chronic course [5, 6], based on thefact that a progression from an “early form” to the classicform of IC has actually never been reported and that thereare unquestionable differences between entities in terms ofage at onset, cystoscopic features, histopathology, compli-cation patterns, and response to various treatments. Stepby step, the definition of the generic concept changed,though, and IC became to include a variety of painfulconditions, including many patients without bladder in-flammation, while the denomination was unchanged. Inthe meantime, a great variety of treatments were tested,

This article is part of the Topical Collection on Pelvic Pain

M. Fall (*) : R. PeekerDepartment of Urology, Institute of Clinical Sciences, SahlgrenskaAcademy, University of Gothenburg, Sahlgrenska UniversityHospital, SE-413 45 Gothenburg, Swedene-mail: magnus.fall@urology.gu.se

Curr Bladder Dysfunct RepDOI 10.1007/s11884-014-0273-4

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with little consideration to the complete difference of var-ious clinical presentations and with rather limited success.With the objective to get a standard to be used in scien-tific studies, the US National Institute of Diabetes, Diges-tive and Kidney Diseases (NIDDK) defined specific re-search criteria [7]; these were not only widely acceptedfor research but promptly gained clinical acceptance. How-ever, at this stage, the widened disease concept had result-ed in uncertainty on what Hunner’s lesions actually meant,their prevalence, and how they should appear, as can beseen in the report from the NIDDK meeting [8]. Finally,different experts had different opinions on the contents ofthe term IC, an evolution resulting in much confusion inresearch and even more so in the understanding on how totreat sufferers in the best way.

The work of a society founded ten years ago has changedthe attitude of today’s clinical research. The society, initiallydenominated the European Society for the Study of InterstitialCystitis (ESSIC), now the International Association for theStudy of Bladder Pain Syndrome, adopted the task to assessdefinition problems. Schemes were presented on how to ex-amine and classify patients with bladder pain. The importanceof identifying phenotypes was emphasized. A new terminol-ogy was suggested, adapted to international taxonomy [9,10••]. The interest in the divergent spectrum of painful condi-tions among other things resulted in a renewed focus on theclassic type of ICwith Hunner’s lesions, denominated type 3Cin the ESSIC system [10••] (Fig. 1). Evidence is accumulatingsuggesting that this is a distinct and well-defined disease withcharacteristics differing from other forms of bladder painstates as maintained many years ago [5].

Prevalence

There is a female predominance of about 10:1 [3, 11, 12], asex difference still open for an explanation. The first system-atic study on prevalence by Oravisto indicated that IC affectedapproximately 10/100,000 (18/100,000 in women) of the pop-ulation in Finland [11], and at that stage, it can be assumed thatclassic IC represented a substantial part of the study popula-tion. Interestingly, similar figures were obtained in the USAfifteen years later [13]. More recently, it has, however, beenproposed that the prevalence has been much underestimated[14–16]. In line with views like that, thirty years after theOravisto study, Leppilahti et al. [17] found dramatically highfigures in Finland comparing to the results of Oravisto: theprevalence of clinically confirmed probable IC in women was230/100,000 and that of possible/probable IC was 530/100,000. When comparing all studies, uncertainty remains aboutthe true figures due to the use of purely symptomatic diagnos-tic criteria in the majority of studies and varying definitions ofstudy populations. Classic IC seems to be a minor part in mostrecent prevalence studies; the knowledge about the prevalenceof the classic form of IC with Hunner’s lesions remains scant.The distribution varies from 5 to 55 % in various populations,centers, times, and series [4, 6, 12, 18, 19•, 20, 21]. The dra-matic differences reported, with quite high figures in our cen-ter as in Moscow and Taiwan, to give some examples, withlow figures in some centers in the UK and USA (personalcommunications), makes it difficult to explain differencesmerely by a geographical factor. In all likelihood, referral pat-terns and routines of investigation/diagnosis, particularly themandatory use of cystoscopy and bladder distension in somecenters and liberal versus limited willingness to diagnosebladder pain syndrome in others, play major roles in the vary-ing detection rate.

Symptoms of IC versus BPS

The key to the diagnosis of IC and bladder pain syndromes(BPS) is identification of the characteristic symptoms. Thehistory should include general and disease-specific informa-tion, like the degree of symptoms, preferably using two- orthree-day micturition diaries, registering volume and time foreach voiding, and visual analog scales (VAS) to describe thedegree of pain. Such notes can also be used to assess treat-ment. There are also disease-specific questionnaires, such asthe O’Leary–Sant symptom and problem questionnaires, val-idated in several languages [22].

The traditional description of symptoms in classic IC ispain localized to the bladder area: suprapubically, vaginally,in the groins or sacral area, or in the lower abdomen andpelvis. Very typical is increasing suprapubic pain on increas-ing bladder filling resulting in an imperative need to empty the

Fig. 1 The ESSIC system to account for diagnostic measures and resultswhen investigating patients with bladder pain syndrome/ interstitialcystitis. Adapted from: van de Merwe et al. Eur Urol 2008;53:60–7(ref. [10••])

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bladder, sensations relieved by voiding but soon returning.Subsequent reports of complaints have been “pressure,”“burning,” “sharp,” and “discomfort.” Typically, the pain isfelt in the suprapubic region but it can be referred to locationsthroughout the whole pelvis, including the urethra, lower ab-domen, lower back, medial aspect of the thigh, and the ingui-nal area in any combination. In BPS subjects, it is not alwaysrelated to bladder filling and may be constant or waxing andveining. Until now, the common understanding has been thatBPS with its various presentations, including IC, has quitesimilar symptoms. That was probably the leading motive toput all forms of BPS/IC into one basket, resulting in the diag-nostic confusion of later decades. In disagreement with thisopinion, recent observations indicate that there may be dispar-ities in symptoms between patients presenting cystoscopicabnormalities comparing to those without. Rais-Brahamiet al. found differences in the symptomatic profiles betweenyounger and older subjects, older individuals more frequentlypresenting Hunner’s lesions [23], in that respect confirmingprevious observations [6]. The characteristics of pain havebeen found to relate to endoscopic findings [24], and symp-toms as expressed in voiding diaries were found to differ,suggesting that a voiding score could predict the cystoscopicappearance of the bladder [25]. A relation to distress duringbladder filling in patients with bladder changes supportsthat the bladder might be the primary responsible organ,reflected in changes of autonomous circulatory parame-ters at bladder distension not seen in a group withoutchanges [26], although it must be acknowledged there isa wide overlap in the symptoms expressed by subjectswith and without bladder lesions.

Although bladder pain and urinary frequency may be theonly or major complaints in some individuals, others have abroader spectrum of problems, such as allergy, fibromyalgia,vulvodynia, chronic fatigue syndrome, anxiety disorders, anddepression. Obtaining such details in the patients’ reportsmight be of importance in the identification of variousphenotypes and indicate a more widespread pain syn-drome. With reference to pain pattern, two main pheno-types have quite recently been identified [27], howevernot referring to the presence or absence of classic IC.One study actually comparing various symptom mea-sures in classic IC and non-Hunner’s BPS did not revealany statistically significant differences between the twogroups with the pain measures studied, but notably atrend of differences in the way subjects expressed theircomplaints [28]. There should be no surprise if an in-depth analysis in a sufficiently large sample would re-veal that there are significant differences between classicIC with Hunner’s lesions and non-Hunner’s BPS symp-tom profiles, respectively, with more of disease-specific/bladder-specific symptoms in classic IC and more sys-temic pain in patients with BPS.

Cystoscopy

Cystoscopy, preferably combined with bladder distension dur-ing anesthesia, is still mandatory to diagnose classic IC. Ow-ing to the historical development mentioned above, the uro-logical and gynecological communities of today’s knowledgeon how to identify a Hunner lesion is not up to the mark,limiting research as well as clinical practice. The ability toidentify the various features of the lesion is of paramountimportance to get to the correct diagnosis.

There are a number of cystoscopic signs to be noted whenexamining patients with suspect Hunner’s lesions: there is acircumscript, reddened mucosal area with small vessels radi-ating towards a central scar, with a fibrin deposit or coagulumattached to this area. This site ruptures with increasing bladderdistension, with petechial oozing of blood from the lesion andthe mucosal margins in a waterfall manner. A rather typicaledema develops post-distension with varying peripheral ex-tension [5, 10••]. It should be noted that the so-called Hunnerulcer is not a persistent chronic ulcer but rather a distinctiveinflammatory lesion with a characteristic central fragility, pre-senting a deep rupture through the mucosa and submucosawhen provoked by bladder distension [10••]. This fact mightbe one cause of misconceptions, since over the years, contro-versy has developed as to the prevalence and even the actualexistence of this kind of lesion. Many urologists maintain thatHunner’s lesions are rare, or do not exist, and the fact that theyrarely detect them confirms this false impression. On the otherhand, a false-positive identification of a Hunner lesion mightbe the misinterpretation of a previous biopsy site, sometimespresenting small radiating vessels but without signs of inflam-mation and with a quite different appearance of the flat, palecentral scar—with no disposition towards rupture at bladderdistension, however a reason for potential misunderstandingfor a long time [8]. Detection is certainly a matter ofattention and training. Fortunately, the awareness ofthe indispensability of cystoscopy in diagnostics in thisarea is increasing. New means of identification may behelpful and needed. Narrow band is a technique underevaluation with a potential to increase the detection rateof lesions in IC/Hunner’s disease [29•].

The most frequent endoscopic abnormality followinghydrodistension in patients with BPS is punctuated submuco-sal bleedings or glomerulations [3, 9, 30]. More conspicuouschanges like ecchymoses or flame hemorrhages are some-times seen, a possible source of error with the potential ofbeing mistaken for Hunner’s lesions. Although Messing andStamey [4] stated that glomerulations do not occur in the nor-mal bladder, they are in fact not specific for BPS/IC. Investi-gations of a later date have demonstrated their occurrence inpatients without bladder pain [31, 32]. Speculatively,glomerulations may be just a secondary and rather unspecificphenomenon with limited diagnostic significance [18, 33]. In

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patients with non-Hunner’s BPS, multiple, superficial, close-set cracks may occur during bladder distension, sometimes ina cobblestone or serpiginous pattern, especially in thebladder dome and bladder neck, resulting in bleedingspots post-distension, also important to distinguish fromHunner’s lesions [34••].

A quite characteristic finding at the second filling of thebladder in a patient with the classic Hunner type of lesions is avarying degree of edema extending out in the periphery of thelesion. The reaction is thought to be caused by mast cell de-granulation. The edema demarcates the area of more intensiveinflammatory involvement of the bladder wall, although mi-croscopically, the entire mucosa is to some degree affected[34••]. In the non-Hunner type of presentation, a general ede-ma of the bladder mucosa is sometimes seen, but just as oftenthere is no edematous reaction. The identification of Hunner’slesions signifies a well-defined phenotype. The other varyingendoscopic presentations indicate differences, so far of ob-scure significance, however. The therapeutic implications ofthe identification of glomerulations and mucosal cracks, ifany, remain to be determined, too.

The anesthetic bladder capacity is a parameter of impor-tance, since a reduced capacity together with other character-istics is a further indication of classic IC as being a destructiveinflammation that can result in bladder contracture at endstage [6, 19•]; classic IC can produce a progressive reductionin anesthetic bladder capacity over time. This is all but un-heard of in BPS.

Histopathology

The primary purpose of obtaining biopsies in IC/BPS is toexclude potentially harmful conditions such as bladder carci-noma or carcinoma in situ [9, 35]. At cystoscopy, inflamma-tory conditions such as eosinophilic cystitis, tuberculous cys-titis, and various metaplastic reactions can mimic the classicHunner type of disease, although the risk of such confusion issmall. Some of the metaplastic conditions have malignantcounterparts, though, so deep bladder biopsies may be needed,sometimes supplemented by immunohistochemical stainingof specimens.

Biopsy retrieval and histopathologic examination is ofgreat value in diagnosing classic IC and not the least to illus-trate the dramatic differences between IC and BPS [5, 18, 36]and to exclude confusable LUT diseases [10••]. A limitation inordinary practice is that pathologists in general have ratherlimited experience of IC diagnostics, while a conclusive re-port, as in all advanced diagnostic work, calls for a devotedand experienced specialist.

The urothelium as well as the deeper layers must be includ-ed in the specimen. Microscopic features are not very distinc-tive in non-ulcer disease, but in contrast, a number of findings

are more or less pathognomonic for the classic type of IC.They include the combination of vacuolization and urothelialdetachment, perineural cell infiltrates, neutrophil and eosino-phil granulocytes, and lymphocyte and plasma cell infiltrateswith involvement of deeper layers of the bladder wall [34••,37]. Of special interest is a rather unique mast cell responsecomprising two distinct mast cell populations, including mi-gratory capacity of cells [38–40]. Granulation tissue and ger-minative areas are further features of the classic disease, mostlikely as a result of repeated trauma by bladder filling andstretch of the areas of inflammatory involvement [34••].Again, BPS displays no common histopathologic abnormali-ties contrasting to the patients who would be classified ashaving the classic Hunner-type IC [41].

In recent years, understanding of the properties of variouscell systems has developed dramatically and, moreover, thediagnosis with standard staining procedures and light micros-copy can be enhanced with immunohistochemistry and evenmore sophisticated and sensitive amplification techniquessuch as polymerase chain reaction (PCR) in situ and variousblot and array techniques [42, 43]. One example is the appli-cation of tryptase staining for mast cells, making the oldertoluidine blue and even more so naphthol esterase stainingtechniques obsolete [40, 44]. Hence, the precision of the di-agnosis has improved and the problem of investigator depen-dence is somewhat reduced. Mast cells are thought to have apivotal role in classic IC: they can release a number of distinct,biologically active mediators [45] while their significanceseems to be limited in BPS.

To sum up, classic IC has numerous objective histopatho-logic abnormalities. Further study of the biopsies may lead tocrucial insights into pathophysiology with a potential im-pact on treatment. On the other hand, there is as of nownothing to suggest that BPS is even an intrinsic disorderof the bladder [41].

The Role of Markers

Since obviously, the clinical, endoscopic, and histopathologi-cal diagnosis and phenotyping of BPS/IC appears to be prob-lematic in clinical practice, access to easy-to-use, preferablynon-invasive, additional diagnostic tools is desirable. An ac-curate urine or blood biomarker for the diagnosis of IC andBPS would be of tremendous advantage. However, properbiomarker discovery requires detailed knowledge of diseasephenotypes and their local and systemic responses. Suchknowledge is to a great part lacking, and considering hetero-geneity, it is unlikely that one biomarker could cover the rangeof variation in BPS/IC. A distinction of phenotypes has rarelybeen considered, and the manymarker candidates tested so farhave to be regarded as experimental [46].

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An observation of immediate practical importance is thatdetermination of intravesical evaporation of nitric oxide (NO)seems to provide a reliable means to differentiate classic ICfrom other BPS presentations, with a dramatically high evap-oration in IC compared to almost zero in BPS and controls[47••] (Fig. 2). Investigations into the mechanisms explaininghigh evaporation of NO have the potential to open up newavenues for research and treatment [48–50]. An advantage ofthis diagnostic method is that it is very easy and simple to use,but a disadvantage is that a special, rather expensive device isrequired. Although further research and experience is re-quired, NO at this stage seems to be a most promising candi-date marker for classic IC. The situation is obviously morecomplex in non-Hunner BPS.

Genetics

There have been suggestions that a genome approach shouldbe applied to the study of urological chronic pelvic pain syn-dromes [51]. The successful use of such tools depends oncarefully defined patient populations, though. If a relevantsystem of phenotyping patients could be accomplished, a sur-vey of the genome should possess a fantastic potential forprogress in treating and understanding IC and BPS. Therehave been some studies suggesting that BPS/IC may have agenetic component but evidence is conflicting [52, 53]. At thisstage, just single studies have focused on genetics in classic ICwith Hunner’s lesions. Tseng et al. [54] performed genome-based expression profiling on biopsy material, using a clusteranalysis model of 40 gene expressions. In summary, theyfound changes termed “bladder remodeling” that can composea long-term consequence of the Hunner-type IC. They sug-gested that the tests can be used for the diagnosis of Hunner-type IC. Blalock et al. [55] looked at gene expression analysisof urine sediments. Their analysis supported selective upreg-ulation of genes in the Hunner lesion group primarily

associated with inflammation. Expression profiles failed todiscriminate non-Hunner-lesion bladder pain syndrome fromcontrols, while patients with the Hunner lesion had increasedpro-inflammatory gene expression in urine sediments, like-wise a potential non-invasive biomarker for the classic-typeIC with Hunner’s lesions.

Treatment of Classic IC

Identification or exclusion of Hunner’s lesions should bea cornerstone in BPS/IC diagnostics. Local ablation oflesions is the therapy of choice in patients with theclassic Hunner type of disease, with a good to excellenteffect in up to 90 % of patients [56–59], one of reallyfew options with very good efficacy. Today, this kind oftreatment is acknowledged as first line in IC withHunner’s lesions. The earlier such lesions are identified,the shorter the period the patient has to suffer fromexcruciating symptoms. It is important to resect/fulgurate all lesions to achieve remission of symptoms.The duration of the response may be quite variable,from some months up to several years [57]. Whichmethod of ablation to use is a matter of personal pref-erence since at this stage no comparison of techniqueshas been made. We prefer complete transurethral resec-tion, performed with a minimum of coagulation, withthe assumption that an operation with less coagulationof tissue would entail the smallest risk to aggravatebladder contracture, a well-known complication of clas-sic IC. Obviously, ablation is not applicable in BPS.

Endoscopic injection treatment is another technique,used by, e.g., Cox et al. [60], injecting triamcinoloneinto lesions, with 70 % improvement. A further option,especially useful in classic IC, is cyclosporine A. Supe-riority over Elmiron has been demonstrated [61]. In thevery refractory case, cyclosporine A can have an effecteven in patients resistant to local ablation treatment[62], and it is noteworthy that NO can be used as amarker of the effect of this drug in classic IC, ESSICtype 3 patients [63].

Many studies on quite dissimilar treatment modalities haveindicated marked differences in the effect on symptoms whencomparing classic IC to other presentations of BPS, with morefavorable results in IC, like with TENS [64], sodiumpentosanpolysulfate [65], and reconstructive surgery[66–68], while interestingly an exception from that rule wasthat no difference in the effects of onabotulinum toxin Atreatment was found between classic Hunner’s diseaseand non-Hunner’s BPS [69]. Taken together, however,the differences certainly involve strong arguments for aseparation of IC from BPS.

Fig. 2 Nitric oxide level in parts per billion (ppb) from BPS type 3C/classic IC patients, non-Hunner BPS/non-ulcer IC patients, and controls.Note logarithmic scale. From: Logadottir, Y. Dissertation, University ofGothenburg, 2012: Bladder Pain Syndrome/Interstitial Cystitis. Studieson classic BPS/IC, ESSIC type 3C, with special reference to role of nitricoxide. ISBN 978-91-628-8534-2, with permission

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Concluding Remarks

The classic Hunner disease (BPS type 3C according to theESSIC classification) is a well-defined condition that fulfillsthe requirements of the denomination interstitial cystitis:There are histological signs of a marked inflammation in thebladder submucosa and musculature (the bladder intersti-tium), and treatment of these lesions produces almost univer-sal relief of symptoms. Interstitial cystitis affects middle-agedor older people, again in contrast to BPS, usually with onset inyounger years. In fact, the classic Hunner-type disease is whatfrom the beginning was meant with the term and disease in-terstitial cystitis. We have now come full circle and returned towhat was originally understood by the name interstitial cysti-tis, a fact attracting increased interest ([70], with comments).

When looking generally on functional urology, one may bestruck by the fact that during later decades, we have developedgeneric umbrella terms like OAB, LUTS, and IC, sometimesused as a basis for therapeutic trials, then ignored the fact thatrelevant phenotyping is a sine qua non requirement for atarget-oriented approach and successful treatment. On thecontrary, in urologic oncology, such understanding impreg-nates treatment protocols. For the benefit of our patients, inBPS/IC, it is time for a separation of BPS and IC. Classic IC isa well-defined entity with multiple unique characteristics,those characteristics giving a potential for rational, pharmaco-logical treatment if further investigated. BPS, on the otherhand, seems to include a heterogenic composition of condi-tions calling for broad attempts to be more closely explored.

Acknowledgments This work was supported by the University ofGothenburg ALF project no. 7582 and Anna-Lisa and Bror BjörnssonsResearch Foundation.

Compliance with Ethics Guidelines

Conflict of Interest Magnus Fall and Ralph Peeker declare that theyhave no conflict of interest.

Human and Animal Rights and Informed Consent This article doesnot contain any studies with human or animal subjects performed by anyof the authors.

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