International Journal of Urology (2016)
13121
Case Report
Novel strategy for cystitis glandularis: Oral treatment with
cyclooxygenase-2 inhibitor
Nae Takizawa,1 Tomoaki Matsuzaki,1 Teppei Yamamoto,1,† Takao Mishima,1 Chika Miyasaka,2
Susumu Tanaka,3 Hidefumi Kinoshita,1 Yoshiko Uemura,2 Hisao Yamada3 and Tadashi Matsuda1
Departments of 1Urology and Andrology, 2Pathology and Laboratory Medicine, and 3Anatomy and Cell Science, Kansai Medical
University, Hirakata, Osaka, Japan
Abbreviations & Acronyms
CG = cystitis glandularis
COX = cyclooxygenase
NSAIDs = non-steroidal
anti-inflammatory drugs
TUR-BT = transurethral
resection of a bladder tumor
Correspondence: Tadashi
Matsuda M.D., Department of
Urology and Andrology, Kansai
Medical University, 2-3-1
Shinmachi, Hirakata, Osaka
573-1191, Japan. Email:
matsudat@hirakata.kmu.ac.jp
†Present address: Department of
Urology, Nagano Municipal
Hospital, Nagano, Japan
Received 21 December 2015;
accepted 7 April 2016.
© 2016 The Japanese Urological Association
doi: 10.1111/iju.
Abstract: Cystitis glandularis, a proliferative disease of the bladder, is resistant to
antibiotics, non-steroidal anti-inflammatory drugs, anti-allergy drugs and transurethral
resection. Cystectomy or partial cystectomy is occasionally required for refractory
cystitis glandularis. It has not been defined if cystitis glandularis is a premalignant lesion.
We experienced a case of remission from cystitis glandularis after combination of oral
treatment with selective cyclooxygenase-2 inhibitor, celecoxib and transurethral
resection. Immunohistochemistry showed positive signals of cyclooxygenase-2 in the
epithelium of pretreatment specimens, suggesting the pathophysiological role of
cyclooxygenase-2 in cystitis glandularis. Here, we show the effectiveness of celecoxib
against cystitis glandularis for the first time. Celecoxib could be one of the therapeutic
strategies for cystitis glandularis.
Key words: cyclooxygenase-2, cyclooxygenase-2 inhibitor, cystitis glandularis, intestinal
metaplasia, intestinal type.
Introduction
CG is a proliferative disease of the bladder. Although it has been reported that CG might con-
vert to adenocarcinoma, the risk of malignancy is controversial.1 CG is known to be refrac-
tory, and the optimal treatment has not yet been established. CG is categorized into typical
type and intestinal type.2 Intestinal type is characterized by the presence of abundant mucin-
secreting goblet cells, and shows occasional extravasation of mucin into the surrounding tis-
sues. CG develops from and merges unnoticeably with von Brunn’s nests. It is suggested that
CG is a normal feature of the bladder mucosa.3 In contrast, chronic inflammation is suggested
to play a pathophysiological role in CG.4 Recent studies have shown that COX-2 is overex-
pressed in CG.5 COX-2 is an inducible enzyme that is especially present in inflammatory tis-
sues and various tumors.6–8 COX-2 functions as an inflammatory mediator to catalyze the
conversion of free essential fatty acids to prostanoids, which are known to be vasodilators.
Vasodilation with prostanoids induces migration of lymphocytes. As a result of increased
migration of lymphocytes, inflammatory diseases are exacerbated. We report here the first
case of CG to be improved by COX-2 inhibitor and TUR-BT.
Case report
A 37-year-old man presented to Kansai Medical University Hospital, Osaka, Japan, complain-
ing of gross hematuria. Microscopic examination of urinary sediment showed no red or white
cells, and urine culture was negative. Abdominal ultrasound and computed tomography
showed a bladder tumor concomitant with wall thickness and left mild hydronephrosis. Blood
urea nitrogen and serum creatinine levels were 12 and 0.60 mg/dL, respectively. Cystoscopy
showed that the sessile tumor expanded through the trigone, left wall and posterior wall
(Fig. 1). The tumor obscured the left ureteral orifice. The patient underwent TUR-BT under
spinal anesthesia. The tumor was resected completely. Pathological findings showed the pres-
ence of abundant mucin-secreting goblet cells without evidence of malignancy; therefore, we
diagnosed intestinal type CG (Fig. 2).9 One month later, cystoscopy showed recurrence of
CG in its former position. While referring to published reports of CG, we attempted to treat
the patient with antibiotics, NSAIDs (loxoprofen sodium hydrate, 60 mg three times daily),
1
N TAKIZAWA ET AL.
(a) (b)
100 µm
Fig. 2 Pathological findings. Histopathological analysis of the tumor showed
many goblet cells in the bladder epithelium (arrow head) and extravasation
of mucin (arrow). Pathological findings indicated intestinal type CG. There
was no evidence of malignancy.
steroid pulse therapy and anti-allergy drugs in addition TUR-
BT. These treatments had no effect on the cystoscopic find-
ings. We repeated TUR-BT 1 year after the initial operation,
but the pathological findings were similar to before, namely,
CG. The patient was treated with steroid maintenance therapy
2 © 2016 The Japanese Urological Association
Fig. 1 Cystoscopic findings at the initial visit. (a)
Cystoscopy showed expansion of the sessile
tumor through the trigone, left wall and posterior
wall of the bladder. Normal mucosa is observed
at the dome and right wall of the bladder. (b) The
left ureteral orifice is obscured by the tumor.
(prednisolone 10 mg/day) for 6 months after the second
TUR-BT. This multidisciplinary therapy yielded a small, but
not marked, improvement in CG on cystoscopy. A third
TUR-BT was carried out. Postoperatively, we started oral
treatment with the COX-2 inhibitor, celecoxib (100 mg twice
daily; Astellas Pharma, Tokyo, Japan). Although the use of
celecoxib is not applied to cystitis glandularis, the indication
of celecoxib includes postoperative analgesia and an anti-
inflammatory effect. We explained the off-label use of cele-
coxib to the patient and obtained his consent. Three months
later, cystoscopy showed a normal appearance (Fig. 3). We
retrospectively analyzed the initial TUR-BT specimens by
immunohistochemical staining with COX-2 antibody, which
was carried out at Kyodo Byori (Hyogo, Japan). Three-micro-
meter-thick sections of initial TUR-BT specimens were
deparaffinized, hydrated and incubated with rabbit antihuman
COX-2 immunoglobulin G (C295; IBL, Gunma, Japan) after
quenching of endogenous peroxidase and blocking by Block-
ing One (Nacalai Tesque, Kyoto, Japan). Sections were incu-
bated with goat horseradish-peroxidase-conjugated antirabbit
immunoglobulin G (Nichirei Biosciences, Tokyo, Japan) and
3,30 -diaminobenzidine tetrahydrochloride. Counterstaining
was carried out with Mayer hematoxylin. We detected signals
for COX-2 in the epithelium of abundant mucin-secreting
goblet cells (Fig. 4a) and in common glandular architecture,
as for CG (Fig. 4b). The patient is in good health, and left
Fig. 3 Cystoscopic findings at 3 months after
treatment with COX-2 inhibitor. Cystoscopic
findings showed normal appearance. No apparent
tumor was identified.

(a)
Fig. 4 COX-2 in initial TUR-BT tissue. Different
sections from the same initial TUR-BT specimen.
(a) Mucin gave the cytoplasm a clear appearance.
The remainder of the cytoplasm occupied by
mucin had positive signals for COX-2 (arrow
heads). (b) Cytoplasmic staining of COX-2 in the
epithelium with a common incidental architecture,
as for CG (arrows).
hydronephrosis and gross hematuria disappeared after treat-
ment with the COX-2 inhibitor and TUR-BT.
Discussion
CG is a proliferative disease of the bladder. Many cases of CG
are resistant to antibiotics, NSAIDs, anti-allergy drugs and
TUR-BT.10 The hypothesis that CG is a premalignant lesion is
controversial. Several small studies have reported conversion of
CG to adenocarcinoma; however, this has not been supported
by a large clinical study.1 Li et al. have speculated that CG is
converted into a premalignant lesion in the presence of carcino-
gens.5 In contrast, Corica et al. have concluded that intestinal
type CG is not a strong risk factor for adenocarcinoma or
urothelial carcinoma.1 They found no evidence of carcinoma in
53 patients with intestinal metaplasia at >10 years’ follow up.
Smith et al. reported that new urothelial carcinoma developed
3 months after diagnosis only in a single case of 136 patients
with CG.4 They retrospectively diagnosed concurrent carcinoma
in seven of 19 patients with intestinal metaplasia and in 39 of
117 patients with florid CG (mean follow-up time 4.4 years).4 It
remains to be elucidated if CG is related to adenocarcinoma.
Therefore, periodic endoscopic evaluation of patients with CG
is recommended.4 The risk of the adenocarcinoma in the short
term is considered to be low for CG patients.1,4 There might be
no need to follow up these patients closely.
Intestinal metaplasia has several similarities to colonic
mucosa, including morphology and gene expression pattern
of some markers,9 and celecoxib, a non-steroidal anti-inflam-
matory COX-2 selective inhibitor, is effective in preventing
colorectal adenoma.11 The inflammatory factor COX-2 is
overexpressed in CG.5 Therefore, we used celecoxib for treat-
ment of our patient with refractory CG. In the present case,
TUR-BT, antibiotics, other NSAIDs, steroid pulse therapy,
steroid maintenance therapy and anti-allergy drugs were inef-
fective. The celecoxib dose was almost 400 mg twice daily
when used in expectation of an anticancer effect.8,11 We pre-
scribed celecoxib 100 mg twice daily, as ≥400 mg/day has a
risk of serious cardiovascular complications.11 We also con-
sider that 200 mg celecoxib might have a moderate anti-
inflammatory effect with the degree not to reach an anti-
cancer effect and still be effective against intestinal type CG.
This dose of celecoxib improved cystoscopic findings and
achieved remission in the present case of CG.
As expected, immunohistochemical staining of initial TUR-
BT specimens showed positive signals for COX-2. Bladder
mucosal biopsy after treatment with celecoxib has not been
© 2016 The Japanese Urological Association
Novel strategy for cystitis glandularis
(b)
100 µm 100 µm
obtained yet owing to a lack of patient consent, but cystoscopic
findings showed normal appearance and no apparent tumor.
Therefore, histopathological analysis could show a normal
level of COX-2 in the bladder mucosa in the present case with
remission. Inhibition of COX-2 resulted in a new transcrip-
tional profile and induced anti-inflammatory activity.8 There
was also a significant reduction in the Ki-67 proliferation mar-
ker.8 Thus, we speculated that relief of inflammation and con-
trol of gene expression after inhibition of COX-2 by celecoxib
could have had beneficial effects in our case of CG. The pre-
sent case is the first report of celecoxib-induced remission of
CG. Further research is required to clarify the mechanisms
involved in the development of CG. COX-2 inhibition could be
a useful therapeutic strategy for CG.
Conflict of interest
None declared.
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