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INTERNATIONAL NEUROUROLOGY JOURNALpISSN 2093-4777
eISSN 2093-6931

Review Article

Volume 19 | Number 2 | June 2015 pages 131-210

INTERNATIONALNEUROUROLOGY JOURNAL

Int Neurourol J 2021;25(2):99-110
https://doi.org/10.5213/inj.2142084.042
pISSN 2093-4777 · eISSN 2093-6931

Official Journal of
Korean Continence Society / Korean Society of Urological Research / The Korean Children’s Continence
and Enuresis Society / The Korean Association of Urogenital Tract Infection and Inflammation

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Current Understanding and Future Perspectives of Interstitial
Cystitis/Bladder Pain Syndrome
Tomohiro Ueda1, Philip M. Hanno2, Ryoichi Saito1,3, Jane M. Meijlink4, Naoki Yoshimura1,5
Department of Urology, Ueda Clinic & Comfortable Urology Network, Kyoto, Japan
Department of Urology, Stanford University School of Medicine, Stanford, CA, USA
3
Department of Urology and Andrology, Kansai Medical University, Osaka, Japan
4
International Painful Bladder Foundation, Naarden, The Netherlands
5
Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
1
2

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic disease characterized by suprapubic pain and lower urinary
tract symptoms. Perhaps because of the heterogeneous nature of this disease and its multifactorial etiology, clinical trials in allinclusive populations of IC/BPS patients without phenotyping in the last decade have mainly failed to discover new therapeutic modalities of IC/BPS. Thus, phenotyping IC/BPS, aimed at identifying bladder-centric and/or bladder-beyond pathologies,
including cystoscopic observation of Hunner or non-Hunner lesions of the bladder mucosa, is particularly important for the
future of IC/BPS management. Based on recent discussions at international conferences, including the International Consultation on IC, Japan, it has been proposed that Hunner-lesion IC should be separated from other non-Hunner IC/BPS because ofits distinct inflammatory profiles and epithelial denudation compared with non-Hunner IC/BPS. However, there are still nostandard criteria for the diagnosis of Hunner lesions other than typical lesions, while conventional cystoscopic observations
may miss atypical or small Hunner lesions. Furthermore, diagnosis of the bladder-centric phenotype of IC/BPS requires confirmation that identified mucosal lesions are truly a cause of bladder pain in IC/BPS patients. This review article discusses thecurrent status of IC/BPS pathophysiology and diagnosis, as well as future directions of the proper diagnosis of bladder-centric
IC/BPS, in which pathophysiological mechanisms other than those in inflammatory pathways, such as angiogenic and immunogenic abnormalities, could also be involved in both Hunner-lesion IC and non-Hunner IC/BPS. It is hoped that this newparadigm in the pathophysiological evaluation and diagnosis of IC/BPS could lead to pathology-based phenotyping and newtreatments for this heterogeneous disease.
Keywords: Interstitial cystitis; Bladder pain syndrome; Hunner lesion; Cystoscopy; Narrow-band imaging; Angiogenesis• Conflict of Interest: T. Ueda reports personal fees from Kyorin, Seikagaku and Japan Tobacco. P.M. Hanno has reports personal fees from Seikagaku, Ironwood, Imbrium, and HTL Biotech. N. Yoshimura reports personal fees from Kyorin and Astellas. R. Saito and J.M. Meijlink reportno competing interests.

INTRODUCTION
Bladder pain syndrome (BPS) is an umbrella term encompassing bladder pain conditions, which include interstitial cystitis
Corresponding author: Tomohiro Ueda https://orcid.org/0000-0002-9611-5691
Department of Urology, Ueda Clinic, 6F CUBEOIKE, 599 Bano-cho, Anekojisagaru, Karasuma-dori, Nakagyo-ku, Kyoto 604-8172, Japan
Email: tom328177@gmail.com
Submitted: March 9, 2021 / Accepted after revision: April 13, 2021

(IC) with Hunner lesions, commonly seen in women and frequently confused with chronic pelvic pain syndrome/nonbacterial chronic prostatitis in men. BPS also often overlaps with irritable bowel syndrome, which occurs mainly in the large intesThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Copyright © 2021 Korean Continence Society

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Ueda, et al. • Current Understanding and Future Perspectives of IC/BPS

tine, and endometriosis, which may involve not only the uterus,
but also the ovaries and bladder in women. Although there is
still no globally accepted definition of IC/BPS, clinical trials in
all-inclusive populations of IC/BPS patients without phenotyping in the last decade have mainly been unsuccessful. Thus,
phenotyping IC/BPS, aimed at identifying bladder-centric and/or bladder-beyond pathologies responsible for bladder pain andassociated symptoms, is of paramount importance for the development of effective treatment modalities for IC/BPS. This
review article will summarize current knowledge and future
perspectives of IC/BPS diagnosis and treatment targets, with aparticular focus on identifying bladder-centric IC/BPS pathophysiology.

HISTORICAL AND CURRENT UNDERSTANDING
OF IC/BPS: THE FUTURE (PRESENT) SEEN
FROM THE PAST
Historical View of IC/BPS
IC was initially reported as “a rare type of bladder ulcer inwomen” by Hunner [1] with characteristic changes in the bladder wall, which are known today as Hunner lesions [2] and associated with typical symptoms such as bladder pain, urinary
frequency, and an urgent need to void [1,3-5]. In 1988, the National Institute of Diabetes and Digestive Kidney Diseases (NIDDK) developed a set of research criteria for IC. However,these criteria proved to be too strict for widespread clinical use[3]. Therefore, a more inclusive, symptom-based definition wasdeveloped and published as a guideline by the American Urological Association (AUA) in 2011 [3]. IC/BPS is defined in the
AUA guideline as “an unpleasant sensation (pain, pressure and/or discomfort) associated with lower urinary tract symptoms of
more than 6-week duration, in the absence of infection or otheridentifiable causes” [3]. Cystoscopic findings are not a part ofthe definition, which is a purely symptom-based diagnosis of
exclusion. In contrast, an East Asian guideline [6] divided IC/
BPS into 3 groups: (1) Hunner IC (HIC)/BPS with Hunner lesions, (2) non-Hunner IC /BPS with mucosal bleeding after hydrodistension in the absence of Hunner lesions, and (3) hypersensitive bladder (i.e., BPS) with no proven bladder pathology
or other confusable disease. These categories are consistent with
BPS type 3, type 2, and type 1, respectively, in the classificationof the International Society for the Study of Bladder Pain Syndrome [7].
It has recently been reported that non-Hunner IC/BPS and

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HIC are distinct pathological entities, with the latter being characterized by significant lymphocytic infiltration (≥200 cells/mm2)
and epithelial denudation compared with non-Hunner IC/BPS
patients [8]. A Hunner lesion seen in HIC patients is not an“ulcer,” but rather a distinctive inflammatory lesion presenting
as a reddened mucosal area with fragile microvessels radiating
towards a central scar [9]. However, it has been demonstrated
that mucosal bleeding after hydrodistension (i.e., glomerulations) seen in non-Hunner IC/BPS patients does not correlatewith symptoms and is also found in patients without IC/BPS[10]. In this regard, the recently revised East Asian guideline categorized IC/BPS into 2 main entities: Hunner-type IC and nonHunner BPS [11]. However, bladder angiogenesis seen in nonHunner IC and HIC patients has also been recognized as animportant characteristic in other chronic inflammatory diseases
such as diabetic retinopathy, atherosclerosis, and inflammatory
bowel disease [12,13]. Thus, although glomerulations shown by
mucosal bleeding upon bladder hydrodistension are not unique
to IC/BPS, underlying microvascular changes in the bladdermucosa due to angiogenesis could be another important component of the pathophysiology of both non-Hunner IC and HIC
in addition to significant inflammation in the HIC subtype, andcould potentially demonstrate a clinically significant phenotypic
differentiation between non-Hunner IC and BPS without apparent bladder pathologies based on future research findings.

Personal Experiences of IC/BPS
More than a quarter of a century has passed since one of theauthors (TU) became deeply involved in the clinical care of patients with IC/BPS, particularly IC with cystoscopically identified bladder pathologies, including Hunner lesions. It was whileworking at a Cancer Institute hospital in Tokyo, Japan in 1990
and encountering patients suffering from bladder pain similar
to that of IC as an adverse reaction to intravesical bacillus
Calmette-Guerin immunotherapy for bladder carcinoma in situ
(CIS) that he was first motivated to become involved in IC/BPS.
Some CIS patients who took the oral antiallergic agent suplatast
tosilate (IPD) inexplicably experienced relief from their bladderpain. Later, after transferring to a local, general core hospitalnear Kyoto, Japan, he had a patient with refractory IC/BPS andsevere bladder pain. Although she appeared to be a completely
healthy, middle-aged woman, she said, “I want my bladder taken out.” A cystoscopic examination revealed typical Hunner lesions (Fig. 1), and oral IPD therapy led to symptomatic relief.
Experiences with 4 patients treated with IPD were subsequently
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Fig. 1. Cystoscopic images of Hunner lesions. Typical Hunner lesions, based on the definition in the ESSIC classification (BPS type 3),
in 4 different IC/BPS patients are shown. ESSIC, International Society for the Study of Bladder Pain Syndrome; BPS, bladder pain syndrome; IC, interstitial cystitis.
Table 1. Major outcomes of the International Consultation on Interstitial Cystitis, Japan (ICICIJ)ICICIJ

Major outcomes

ICICJ #1 (2003)·	175 Participants from 17 countries attended the first international meeting, which was a global kick off meeting for interstitial
cystitis with both doctors and patients

ICICJ #2 (2007)·	200 participants from 25 counties·	Definition of IC: bladder pain syndrome & BPS/ ICICICJ #3 (2013)·	96 Participants from 16 countries·	Phenotyping of IC based on pathophysiology

ICICJ #4 (2018)·	Discussion on the definition of IC as bladder pain syndrome with Hunner lesion·	179 Participants from 20 countries·	Consensus that Hunner lesion IC/BPS with significant inflammation in the bladder can be categorized as a separate disease
entity from other BPS conditions

BPS/IC, bladder pain syndrome/interstitial cystitis.

presented as a report on the clinical effects of IPD at the 1998
annual meeting of the AUA, and the results of IPD treatment
were published in the Journal of Urology in 2000 [14]. Furthermore, this presentation at the 1998 AUA meeting offered aunique opportunity to make the acquaintance of key opinion
leaders in the field of IC/BPS in the US, who encouraged theorganization of international meetings with world experts in
IC/BPS with the aim of achieving consensus on the definition
and treatment of IC/BPS.

Achievements Through the Meetings of the International
Consultation on Interstitial Cystitis, Japan
In 2003, the first meeting of International Consultation of Interstitial Cystitis, Japan (ICICJ) was successfully held and attended by 175 IC scientists from all over the world as well as anumber of patient advocates. The objectives of the meeting included: (1) drawing public attention to IC/BPS, (2) allowing
opinion exchanges among experts, and (3) presenting new
findings. The conference was subsequently held again in 2007,
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2013, and 2018 (Table 1) [15-18].
During the meetings, we witnessed much discussion and debate regarding the differences in the definition, diagnosis, andtreatment of IC/BPS in one and the same patient entirely depending on the healthcare system and culture of the countries/
regions where the participants resided. For example, in Asia
and Europe, IC/BPS was diagnosed by performing cystoscopy
and trying to define IC based on Hunner lesions and otherbladder findings as a starting point, whereas in North America,
IC/BPS was diagnosed as part of a symptom-based syndrome
without a mandatory cystoscopic examination. Fifteen years
ago, a research network program was established in the US
known as the Multidisciplinary Approach to the Study ofChronic Pelvic Pain (MAPP) set up by the NIDDK. In this program, attempts have been made to classify IC/BPS through diagnostic methods other than cystoscopy or histological findingsof the bladder alone, including urinary markers and brain imaging techniques. In addition to the MAPP efforts, several
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HIC withsevere pain

A
CD44

TGF-β

PD-ECGF/TP

Non-Hunner IC
with mild pain

B

Fig. 2. Overexpression of angiogenic factors in the bladder of IC/BPS patients. The images show the results of immunohistochemical
staining for epithelial and submucosal CD44, transforming growth factor (TGF)-β, and PD-ECGF/TP in bladder tissue sections frompatients with IC/BPS. (A) Positive staining in the severe IC type (Hunner-type IC [HIC] patients with severe pain) is seen in the deeper part of the submucosal layer. (B) Positive staining in the mild IC type (non-Hunner-type patients with relatively mild pain) is present along the basement membrane of the bladder epithelium; ×200 magnification. (Reproduced from Ueda T, et al. J Urol
2002;167:347-51 [32]). PD-ECGF, platelet-derived endothelial cell growth factor; TP, thymidine phosphorylase; IC, interstitial cystitis;
BPS, bladder pain syndrome.
new investigational drugs in IC/BPS patients diagnosed primarily on the basis of symptoms alone in accordance with thecurrent U.S. Food and Drug Administration guidance [19].
However, none of these trials have led to new approved treatments in the last decade. These outcomes highlight the importance of IC/BPS phenotyping, especially the differentiation of
IC/BPS patients with cystoscopically identified Hunner lesions
from non-Hunner IC/BPS, prompting reconsideration of thediagnostic approach [20]. Active discussions on this topic werealso held at the ICICJ meetings, and the 2018 conference finallyreached a consensus that HIC with significant inflammation in
the bladder is clinically and pathologically distinct from nonHunner IC/BPS and may be categorized as a separate disease
entity called “Hunner lesion disease (HLD),” distinct from other BPS conditions [18,20]. The importance of IC/BPS phenotyping using cystoscopy-based detection of Hunner lesions has
been further supported by recent articles, including some from
North America [20-23].
In addition, IPD was the first drug investigated in a clinical
trial as drug therapy for IC/BPS in Japan. While this IPD clinical trial unfortunately did not meet the approval criteria set by
the national health insurance coverage in Japan, it nevertheless

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revealed the potential implication of immune mechanisms andthe important role of angiogenic factors in the pathogenesis of
IC/BPS [14] (Fig. 2). Furthermore, the use of hydrodistension
for the diagnosis of IC/BPS is known to have therapeutic benefits [24], which may shed light on the underlying pathogenesisof glomerulations after hydrodistension (Fig. 3). In other words,
there are newly developed blood microvessels in the submucosathat are specific to IC/BPS and differ from normal blood vessels. Therefore, hydrodistension-induced stretching of the bladder wall could cause these microvessels to easily rupture andbleed [25] (Fig. 3).
However, a recent review of studies concluded that glomerulations caused by bladder hydrodistension are not a phenomenon unique to IC/BPS [10]. Similarly, the potassium chloride(KCL) test (potassium sensitivity test) [26] proposed by Parsons
was also assessed as having low sensitivity and low specificity[27]. However, to date, underlying bladder conditions thatmight explain why glomerulations occur after hydrodistension
and why pain is not triggered by potassium in some IC/BPS patients have not been fully clarified. Thus, we hypothesize thatangiogenesis with microvessel formation in the bladder submucosa could be another important pathophysiological compoInt Neurourol J June 30, 2021

Ueda, et al. • Current Understanding and Future Perspectives of IC/BPSPD-ECGF* (97.4%)

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VEGF** (68.4%)(*/** Negative staining in 5 control cases)
Overexpression ofangiogenic growth factors
Possible angiogenic
mechanism ofglomerulation

Neovascularization with increase in
weak microvessels

RuptureMechanical or congestive stress on thesemicrovessels during distention

Fig. 3. The angiogenic mechanisms inducing glomerulations. In IC/BPS bladders, overexpression of angiogenic factors such as VEGF
and PD-ECGF includes neovascularization with increases in weak microvessels, leading to rupture of microvessels during bladder distention, seen as glomerulations during cystoscopy (Reproduced from Ueda T, et al. J Urol 2002;167:347-51 [32]). IC, interstitial cystitis;
BPS, bladder pain syndrome; VEGF, vascular endothelial growth factor; PD-ECGF, platelet-derived endothelial cell growth factor.
nent in the bladder of HIC and non-Hunner IC/BPS, in addition to inflammatory changes in HIC bladders, despite the factthat glomerulation upon hydrodistension is not in itself a phenomenon specific to IC/BPS bladders. Fig. 4 summarizes thepotential immunogenic mechanisms underlying angiogenic
changes in the bladder submucosa of bladder-centric IC/BPS.
Firstly, as part of multiple etiologies, disturbances in the glycosaminoglycan (GAG) layer with increased bladder epithelial
permeability lead to activation of inflammatory responses andoverexpression of angiogenic factors, such as vascular endothelial growth factor (VEGF) and platelet-derived endothelial cell
growth factor (PD-ECGF) in the submucosa. Furthermore,disruption of the GAG layer causes the release of adhesion factors such as CD44 and transforming growth factor-beta, which
are known to bind with angiogenic factors that are present invery small amounts via heparin-binding and become solidified.
This process has been elucidated as part of the wound healing
process; thus, it is considered that the overexpression of angiogenic factors is involved in tissue fibrosis leading to bladder atrophy [25]. Submucosal inflammatory cell infiltration with cytokine/chemokine production, as well as increased bladder epithelial permeability allowing harmful urinary substances such
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as K+ and H+ ions to penetrate the bladder wall, is also presumed to sensitize bladder afferent pathways, especially the Cfiber type, thereby causing IC/BPS symptoms such as pain andurgency (Fig. 4).

FUTURE PERSPECTIVES WITH OURPROPOSALS
Current Problems and Controversies Regarding IC/BPS
Collectively assuming that HLD and non-Hunner IC/BPS is one
disease entity has become a major impediment to identifying
factors responsible for bladder pain
As mentioned above, IC/BPS is part of the pelvic pain spectrumof disorders that can be caused by impairments in the urinary,gynecologic, and gastrointestinal systems; therefore, evaluationof each organ is necessary. In addition, in patients diagnosed
with chronic prostatitis, IC/BPS has been reported as a comorbidity associated with decreases in maximal voided volume per
micturition and maximal bladder capacity during cystoscopy
under local anesthesia. Therefore, a cystoscopic diagnosis may
be helpful for the differential diagnosis of chronic prostatitis
and associated comorbidities [28].
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Fibroblast

H

Fig. 4. Immunogenic and angiogenic pathophysiology of IC/BPS. In bladder-centric IC/BPS, increased bladder epithelial permeability due to disturbances in the glycosaminoglycan (GAG) layer and activation of inflammatory cells including mast cells, T cells, and B
cells has been proposed as part of multiple etiologies. Disturbance of the bladder epithelium, overexpression of angiogenic factors,
such as platelet-derived endothelial cell growth factor (PD-ECGF), occurs in the submucosa. These angiogenic factors are present invery small amounts in the body or bladder under normal conditions. However, angiogenic factor overexpression in IC/BPS may result from abnormalities in GAG because disruption of the GAG layer, which is a protective factor of the bladder epithelium, causes therelease of adhesion factors in the GAG layer, such as CD44 and TGF-β (an adhesion molecule), which are known to bind with angiogenic factors that are present in very small amounts via heparin-binding and become solidified. This has been elucidated as part of thewound healing process; thus, it is considered that overexpression of angiogenic factors is involved in tissue fibrosis leading to bladderatrophy. The onset of IC/BPS starts with various insults to the bladder epithelium, for example by previous bacterial infection and/or
harmful substances such as K+ and H+ ions in the urine. These noxious stimuli are detected by inflammatory cells such as type 2 helper
T lymphocytes, which then send signals to activate mast cells. Mast cells play an important role in the inflammatory process to induce
angiogenic factors and immunostimulatory factors to activate other immunocompetent cells. These stimulating factors are presumed
to sensitize bladder afferent pathways, especially the C-fiber type, thereby causing IC/BPS symptoms (pain and urgency). MΦ, macrophage; Eos, eosinophils; IC, interstitial cystitis; BPS, bladder pain syndrome; TGF, transforming growth factor.
Bladder pain related to the nervous, endocrine, and immune
systems
The International Continence Society meeting held in Korea in2002 defined the term “overactive bladder (OAB) syndrome” asa frequency-urgency syndrome with a chief complaint of sudden urinary urgency that is likely to show uninhibited bladdercontractions (i.e., detrusor overactivity) if bladder pressure ismeasured by cystometry. This is where the concept of OAB
originated. However, the frequency-urgency syndrome has previously been used to refer to IC [29] (Fig. 5), suggesting a symptomatic overlap between IC and OAB. Neuromodulation using
Interstim implantation is reimbursed in the United States for
IC/BPS not because it has been approved for this indication,
but because IC/BPS can be identified as part of the frequency/
urgency syndrome, which is used to refer to OAB. Recent stud-

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ies have also indicated considerable overlap between OAB and
IC/BPS symptoms [30]. Therefore, it is necessary to evaluate
whether bladder pain is related to other etiologies, including
OAB induced by lower urinary tract dysfunction, endocrinological abnormalities due to gynecological diseases such as endometriosis, and immunological abnormalities such as inflammatory bowel disease.
Relationship with refractory OAB
Although IC/BPS is a diagnosis of exclusion with regard to
OAB, it has not been specified how OAB should be excluded.
Therefore, in refractory OAB, it can be useful to proactively
perform a cystoscopic examination to confirm the presence orabsence of intravesical lesions including Hunner lesions.

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

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Muscle Artery

Fig. 5. Symptomatic and pathophysiological overlaps between IC and OAB as the frequency-urgency syndrome. Bladder-centric IC
and OAB exhibit pathophysiological changes at a higher degree in the epithelial/submucosal and submucosal/muscle regions, respectively; however, hallmark symptoms such as urgency are often found in both disease conditions. IC, interstitial cystitis; OAB, overactive bladder.
Concepts for classification of pain etiologies, either
bladder-centric or bladder-beyond, or both in IC/BPS

Table 2. Issues on validation of cystoscopic findings in terms ofaccuracy, precision, sensitivity and specificity

Finally, it is important to evaluate whether bladder pain iscaused by bladder lesions or attributable to extrabladder pathophysiology. It should also be noted that bladder-centric andbladder-beyond etiologies may coexist to induce the overall
symptoms in IC/BPS.

Parameter

Future Directions and Proposals
As described above, in order to establish a diagnosis of bladdercentric IC/BPS in patients complaining of bladder pain, the diagnostic criterion is to confirm the presence of a lesion in the bladder mucosa by cystoscopy. However, there are problems concerning the accuracy of cystoscopic diagnosis (Table 2). A review paper presented at the 2018 ICICJ meeting reported that the proportion of Hunner lesions in IC/BPS patients with bladder pain varied greatly among centers, ranging from 5% to 57% [31].
The challenge concerning the accuracy of cystoscopic findings is
to identify what can be used as “true” indicators (Table 2)With regard to glomerulations caused by hydrodistension, aconsensus has been reached that this phenomenon is not specific to IC/BPS [10]. However, it has previously been reported
that overstretching the bladder wall during bladder filling may
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Accuracy

Issues· What is true?
· Glomerulation?, inflammatory cell?, angiogenic factor?,angiogenesis with neovasculization?
· What is Hunner lesion?

Precision· Grading· Decision of severity

Sensitivity · Differentiation; CIS or OAB
Specificity · What is normal?
· Threshold setting
CIS, carcinoma in situ; OAB, overactive bladder.

be responsible for the rupture of newly developed blood microvessels in non-Hunner lesion-containing bladders of IC/BPS
patients [25] and that overexpression of PD-ECGF or VEGF in
the bladder was found in both non-Hunner IC and HIC subtypes with higher expression in the latter than in the former[32]. This means that the underlying condition for neovascularization, particularly involving the overexpression of angiogenic
factors such as PD-ECGF or VEGF, should be considered to be
bladder lesions rather than glomerulations (Fig. 4) [25,32].
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With respect to Hunner lesions, a pathological mechanism involving specific inflammatory cell infiltration has been elucidated [33] and reportedly accompanied by the overexpressionof angiogenic factors [34]. Therefore, further investigation isneeded regarding the angiogenesis-related pathophysiology of
bladder-centric HIC and non-Hunner IC. Additionally, we
have reported that the use of narrow-band imaging (NBI) enables sensitive detection of angiogenesis and neovascularizationin the bladder mucosa during cystoscopy, making it possible toaccurately identify lesions in the bladder mucosa accompanied
by Hunner lesions and new blood microvessel formation (Fig.
6) [35].
Furthermore, we have recently completed a successful, multicenter, randomized, double-blind, placebo-controlled clinical
trial of intravesical KRP-116D, 50% dimethyl sulfoxide(DMSO) solution in IC/BPS patients in Japan [36]. In this trial,
we recruited IC/BPS patients with the bladder-centric phenotype, which was confirmed by the existence of bladder pathologies such as Hunner lesion and/or mucosal bleeding during hydrodistension (i.e., glomerulations). Also, because glomerulations may not be IC/BPS-specific or responsible for bladder
symptoms [10], all study participants were confirmed to exhibit
short-term bladder pain relief following intravesical lidocaine
instillation during the placebo run-in period, verifying thatWhite-light imaging

their symptoms originated in the bladder (i.e., bladder-centric
phenotype). For the primary endpoint, the change in the mean
O’Leary-Sant interstitial cystitis symptom index score was significantly greater in the KRP-116D group than in the placebogroup. Statistically significant improvements for KRP-116D
were also observed in the secondary endpoints, including the
O’Leary-Sant interstitial cystitis problem index, micturition episodes per 24 hours, voided volume per micturition, maximum
voided volume per micturition, numerical rating scale for bladder pain, and global response assessment. Thus, this successfulDMSO clinical trial indicates that careful phenotyping and selection of patients suited to the clinical trial objectives seems
particularly important for the success of clinical trials in IC/BPS
patients who have heterogeneous pathological backgrounds.
The precision of cystoscopic findings
The challenge lies in establishing a diagnostic accuracy scale,such as grading of bladder lesions and a severity assessment
method (Table 2).
Another issue concerning the sensitivity of cystoscopic
findings is diagnostic differentiation from bladder tumors
Where Hunner lesions are concerned, the concurrent use of
NBI can improve detection sensitivity [35]; however, distinNarrowband imaging (NBI)A

B

Fig. 6. Hunner lesions: white-light imaging (A) and narrow-band imaging (B) in 2 patients with IC/BPS. IC, interstitial cystitis; BPS,
bladder pain syndrome.

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Ueda, et al. • Current Understanding and Future Perspectives of IC/BPSguishing Hunner lesions from bladder CIS remains a challenge.
Without a histological examination, the 2 conditions cannot be
differentiated. In cases of OAB, treatment is usually decided on
the basis of symptoms without confirming bladder lesions inpatients complaining of urinary urgency, who are likely to show
uninhibited bladder contractions in urodynamic studies. Therefore, depending on the severity of bladder pain, OAB is very
likely to overlap with IC/BPS (Fig. 5). Particularly in cases of refractory OAB, as well as patients who report urgency and bladder pain, pressure, or discomfort associated with filling, the differential diagnosis of IC/BPS is aided by a determination of
bladder pathology with the aid of cystoscopy and with urodynamic evaluations.
The specificity of cystoscopic findings
As the first step, the criteria for defining the normal bladder areimportant. Thus, knowing the histo-anatomical structure andendoscopic appearance of the normal bladder mucosa is essential. However, unlike gastroenterological screening tests such as
gastroscopy or colonoscopy, we consider that urologists, unfortunately, have very few opportunities to see normal cystoscopic
findings, since cystoscopy is most often performed in patients
who already exhibit some kinds of lower urinary tract symptoms.
Fig. 7 depicts representative cystoscopic images of normal andnon-Hunner IC bladders, which respectively show the whitish,
distensible mucosa with multiple mucosal folds in the former(Fig. 7A), and the stretched, hypervascular mucosa without
mucosal folding in the latter (Fig. 7B). Moreover, in NBI-assisted cystometry, hypervascularity in the reddish bladder mucosa
Normal (white color)

is more easily recognized in non-Hunner IC (Fig. 7C). Therefore, it is potentially a problem that most urologists see the bladder epithelium when it is no longer in a normal state (i.e., abnormal). Therefore, the bladder mucosa that urologists consider
to be normal may often, in fact, already be abnormal, as shownin Fig. 7B and C, possibly causing a delay in diagnosing bladderlesions associated with IC/BPS. In addition, abnormal morphology of the bladder epithelium does not necessarily meanthat it is pathological. It should only be considered to be pathological when an abnormal epithelium is found in association
with bladder pain and other symptoms. Therefore, it is important for the definition of bladder-centric IC/BPS to accurately
identify bladder pathologies such as Hunner lesions or neovascular changes on the bladder mucosal surface and, at the sametime, to confirm that they are responsible for causing bladderpain. Thus, it is necessary to standardize the methodology of
the cystoscopic assessment of Hunner lesions. A recent article
by Ronstrom and Lai presented an informative atlas showing
cystoscopic photos of typical Hunner lesions in IC/BPS patients[37]. However, there is still a need to define atypical or small
Hunner lesions, which will be missed under conventional cystoscopy with white light [35]. In addition, for the diagnosis of
bladder-centric, non-Hunner IC/BPS, the detection of mucosal
hypervascular lesions caused by angiogenesis and differingfrom normal mucosa (Fig. 7) needs to be standardized.
Furthermore, with regard to bladder-centric, non-Hunner
IC/BPS, it is also important to identify whether bladder lesions
are associated with urothelial hyperpermeability, which is induced by defective, non-self-repairing GAG layer and allows

Non-Hunner IC (white color)A

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Non-Hunner IC (NBI)

B

C

Fig. 7. Representative cystoscopic images of the normal bladder (A) and the non-Hunner IC bladder under white-light imaging (B)or narrow-band imaging (NBI) (C). (A) The bladder epithelial mucosa is largely whitish in color with multiple folds on the mucosal
surface in the normal bladder. Furthermore, the normal mucosal epithelium is stretchable in all directions during bladder distention
because it is loosely connected to the underlying muscle layer. (B, C) Abnormal bladder epithelium characterized by stretched, hypervascular mucosa without mucosal folds in the non-Hunner IC bladder, the appearance of which is similar to the so-called “lead pipesign” of ulcerative colitis during colonoscopy. IC, interstitial cystitis.
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urinary substances to penetrate the bladder wall and induce
bladder pain [5]. In this regard, noninvasive bladder imaging
using magnetic resonance imaging has been investigated toevaluate an increase in the bladder mucosal permeability due
to bladder mucosal lesions as a diagnostic method to replace
the KCI sensitivity test, and expectations for the outcomes arehigh [38].
Biomarkers: causes, results, or completely independent
factors?
Various biomarkers have been reported to diagnose IC/BPS
and assess the therapeutic effects. Although there is no doubt
about the changes in expression levels in the bladder or urine, itis necessary to clarify whether these changes result from thehost’s response to the disease (results), are induced by the disease (causes), or occur as completely independent factors (bystanders). For example, in the case of bladder cancer, the aforementioned excessive expression of angiogenic factors in the
bladder mucosa is triggered by the invasion of malignant cells,
whereas the change in angiogenic factors with neovascularization in IC/BPS is considered to be due to the promotion ofhealing in response to inflammation on the host side [32]. Thus,
even in patients presenting with the same symptoms and showing equal overexpression of angiogenic factors as biomarkers,
the underlying pathological mechanisms can be completely different. Therefore, if various biomarkers are detected, each needs
to be investigated with a highly accurate method to determine
whether it is a cause, a result, or just a bystander.
Need for science-based dietary regimens
Finally, although it is common knowledge that urine pH is influenced by diet and that acidic urine enhances bladder pain
and frequent urination, diet modification therapy is often notvigorously enforced in IC/BPS patients [39]. Some studies havealso reported that substances such as potassium and toxic cations in urine can modify lower urinary tract symptoms of IC/
BPS [40] and that various dietary factors including citrus fruits,
tomatoes, spicy food, alcohol, and caffeinated beverages cantrigger a flare (defined as urologic or pelvic pain that is muchworse than usual) in IC/BPS patients [41]. Therefore, further
research in this field of dietary modification is strongly recommended to improve the treatment of IC/BPS.

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CONCLUSION
This review article has summarized the history of research findings on HIC and non-Hunner IC/BPS in the past quarter of acentury and made some critical proposals for the future. Although great efforts have been made regarding the definition ofthis condition, its pathophysiology, and new treatments, various
clinical studies performed in the last decade have unfortunately
so far failed to lead to new treatments, which may indicate that
there has been insufficient effort focused on exploring the etiology, pathogenesis, and phenotyping of this heterogeneous disease.
Therapeutic effects of treatments cannot be obtained unless
we initially address the patients’ symptoms and explore thecause. Despite the tremendous medical advances made by developing many testing modalities and biomarkers, there can be
no successful treatment in the absence of an accurate diagnosis.
Thus, there can be no bright future for IC/BPS without these 3
steps: (1) understanding the symptoms, (2) detecting abnormal
findings in or outside the bladder, and (3) verifying that the abnormality is the cause of the symptoms.

ORCID
Tomohiro Ueda		
Philip M. Hanno		
Ryoichi Saito		Jane M. Meijlink		
Naoki Yoshimura		

0000-0002-9611-5691
0000-0002-6597-9155
0000-0002-3163-8723
0000-0002-0943-2390
0000-0001-8070-1664

AUTHOR CONTRIBUTION STATEMENT·Conceptualization: TU, PH, JM, NY·Project administration: TU·Writing-original draft: TU, NY·Writing-review & editing: TU, PH, RS, JM, NY

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