The main characteristic of urothelial bladder cancer is a clear predisposition to recurrence and disease progression. The aim of this study was to assess the possible relationship between cyclooxygenase-2 (COX-2) immunoreactivity in superficial urothelial bladder carcinoma and tumor grade, stage, number of recurrences and clinical disease progression.
Methods
In this prospective study 70 consecutive patients who underwent transurethral resection for superficial urothelial bladder cancer were included. Tumor slides were immuno-histochemically stained for COX-2, and COX-2 immunoreactivity in tumor and inflammatory stromal cells was categorized as negative or mildly, moderately or strongly positive. Patients were followed up for 2 years, and during this period the possible association of COX-2 immunoreactivity with tumor stage and grade, number of recurrences and progression of disease was evaluated.
Results
COX-2 immunoreactivity in tumor cells was found in 57 (81.4%) patients and did not correlate with tumor grade, stage of disease, number of recurrences, and progression of disease. COX-2 immunoreactivity in inflammatory cells was found in 16 of the 57 patients with COX-2 positive tumors, and was significantly related to the number of recurrences, time to appearance of the first recurrence, and disease progression.
Conclusions
COX-2 immunoreactivity in inflammatory stromal cells adjacent to the COX-2-positive tumor might be useful in clinical practice for selection of patients with a high risk of tumor recurrence and disease progression.
CalvelJ., CordierS., Boccon-GibodL., HemonD.: Tobacco and bladder cancers in males: Increased risk for inhalers and smokers of black tobacco.Int J Cancer,44: 605–610, 1989.
2.
GreeneF.L., PageD.L., BalchC.M., FlemingI.D., MorrowM.: AJCC cancer staging manual.Springer Verlag, New York, 2002.
SteinJ.P., GrossfeldG.D., GinsbergD.A., ErsigD., FreemanJ.A., FigueroaA.J., SkinnerD.G., CoteR.J.: Prognostic markers in bladder cancer: a contemporary review of the literature.J Urol,160: 645–659, 1998.
6.
OosterhuisJ.W., SchapersR.F., Janssen-HeijnenM.L., SmeetsA.W., PauwelsR.P.: MIB-1 as a proliferative marker in transitional cell carcinoma of the bladder: clinical significance and comparison with other prognostic factors.Cancer,88: 2598–2605, 2000.
7.
De Vere-WhiteR.W., DeitchA.D., DaneshmandS., BlumensteinB., LoweB.A., SagalowskyA.I., SmithJ.A.Jr., SchellhammerP.T., StanisicT.H., GrossmanH.B., MessingE., CrissmanJ.D., CrawfordE.D.: The prognostic significance of S-phase analysis in stage Ta/T1 bladder cancer.Eur Urol,37: 595–600, 2000.
8.
MizutaniY., WadaH., OgawaO., YoshidaO., FukushimaM., NonomuraN., MikiT.: Prognostic significance of thymidylate synthase activity in bladder carcinoma.Cancer,92: 510–518, 2001.
9.
GonteroP., CasettaG., ZitellaA., BallarioR., PaccioniD., MagnaniC., MuirG.H., TizzaniA.: Evaluation of p53 protein overexpression, Ki67 proliferative activity and mitotic index as markers of tumor recurrence in superficial transitional cell carcinoma of the bladder.Eur Urol,38: 287–296, 2000.
10.
KamaiT., TakagiK., AsamiH., ItoY., OshimaH., YoshidaK.I.: Decreasing of p27 (Kip1) and cyclin E protein levels is associated with progression from superficial into invasive bladder cancer.Br J Cancer,84: 1242–1251, 2001.
11.
SgambatoA., MigaldiM., FaragliaB., De AloysioG., FerrariP., ArditoR., De GaetaniC., CapeliG., CittadiniA., TrentiniG.P.: Cyclin D1 expression in papillary superficial bladder cancer: its association with other cell cycle-associated proteins, cell proliferation and clinical outcome.Int J Cancer,97: 671–678, 2002.
12.
LeissnerJ., HohenfellnerR., ThüroffJ.W., KoppenC., WolfH.K.: Prognostic significance of histopathological grading and immunoreactivity for p53 and p21/WAF1 in grade 2 pTa transitional cell carcinoma of the urinary bladder.Eur Urol,39: 438–445, 2001.
13.
GridleyG., McLaughlinJ.K., EkbomA., KlareskogL., AdamiH.O., HackerD.G., HoverR., FraumeniJ.F.Jr.: Incidence of cancer among patients with rheumatoid arthritis.J Natl Cancer Inst,85: 307–311, 1993.
14.
SuhO., MettlinC., PetrelliN.J.: Aspirin use, cancer and polyps of the large bowel.Cancer,72: 1171–1177, 1993.
WendumD., MasliahJ., TrugmanG., FlejonJ.F.: Cyclooxygenase-2 and its role in colorectal cancer development.Virchows Arch,445: 327–333, 2004.
17.
TsujiM., DuBoisR.N.: Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin endoperoxide synthase 2.Cell,83: 493–501, 1995.
18.
ShweikiD., ItinA., SofferD., KeshetE.: Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initi-ated angiogenesis.Nature,359: 843–845, 1992.
19.
YanS.F., TrittoI., PinskyD., LiaoH., HuangJ., FullerG., BrettJ., MayJ., SternD.: Induction of interleukin 6 (IL-6) by hypoxia in vascular cells. Central role of the binding site for nuclear factor-IL-6.J Biol Chem,270: 11463–11471, 1995.
20.
KarakurumM., ShreeniwasR., ChenJ., PinskyD., YanS.D., AndersonM., SunouchiK., MajorJ., HamiltonT., KuwabaraK.: Hypoxic induction of interleukin-8 gene expression in human endothelial cells.J Clin Invest,93: 1564–1570, 1994.
21.
GrubbsC.J., LubetR.A., KokiA.T., LaehiK.M., MasferrerJ.L., SteeleV.E., KelloffG.J., HillD.L., SeibertK.: Celecoxib inhibits N-buty I-N-(4-hydroxybutyl)-nitrosamine-induced urinary bladder cancers in male B6D2F1 mice and female Fischer-344 rats.Cancer Res,60: 5599–5602, 2000.
22.
OkajimaE., UemuraH., OhnishiS., TanakaM., OhtaM., TaniM., FujimotoK., OzonoS., OkajimaE., HiraoY.: Expression of cyclooxygenase-2 in primary superficial bladder cancer tissue may predict risk of its recurrence after complete transurethral resection.Aktuelle Urol,34: 256–258, 2003.
23.
MohseniH., ZaslauS., McFaddenD., RiggsD.R., JacksonB.J., KandzariS.: COX-2 inhibition demonstrates potent anti-pro-liferative effects on bladder cancer in vitro.Surg Res,15: 138–142, 2004.
24.
KomhoffM., GuanY., ShappellH.W., DavisL., JackG., ShyrY., KochM.O., ShappellS.B., BreyerM.D.: Enhanced expression of cyclooxygenase-2 in high grade human transitional cell bladder carcinomas.Am J Pathol,157: 29–35, 2000.
25.
RistimakiA., NieminenO., SaukkonenK., HotakinenK., NordlingS., HaglundC.: Expression of cyclooxygenase-2 in human transitional cell carcinoma of the urinary bladder.Am J Pathol,158: 849–853, 2001.
26.
ShirahamaT.: Cyclooxygenase-2 expression is upregulated in transitional cell carcinoma and its preneoplastic lesions in the human urinary bladder.Clin Cancer Res,6: 2424–2430, 2000.
27.
FriedrichM.G., TomaM.I., PetriS., HulandH.: Cyclooxygenase-2 promotes angiogenesis in pTa/T1 urothelial bladder carcinoma but does not predict recurrence.BJU Int,92: 389–392, 2003.
28.
ShariatS.F., KimJ.H., AyalaG.E., KhoK., WheelerT.M., LernerS.P.: Cyclooxygenase-2 is highly expressed in carcinoma in situ and Tl transitional cell carcinoma of the bladder.J Urol,169: 938–942, 2003.
29.
ShinkaT., MatsumotoM., OguraH., HiranoA., OhkawaT.: Recurrence of primary superficial bladder cancer treated with prophylactic intravesical Tokyo 172 bacillus Calmette-Guerin: a long term follow-up.Int J Urol,4: 139–143, 1997.
30.
MuldersP.F., van der MeijdenA.P., DoesburgW.H., OosterhofG.O., DebruyneF.M.: Prognostic factors in pTa-pTl superficial bladder tumors treated with intravesical instillations.Br J Urol,73: 403–408, 1994.
31.
KiemeneyLALM, WitjesJ.A., HeijbroeckR.P., KoperN.P., VerbeekA.L., DebruyneF.M.: Should random urothelial biopsies be taken from patients with primary superficial bladder cancer? A decision analysis.Br J Urol,73: 164–171, 1994.
32.
Millan-RodriguezF., Checile-TonioloG., Salvador-BayarriJ., PalouJ., Vicente-RodriguezJ.: Multivariate analysis of the prognostic factors of primary superficial bladder cancer.J Urol,163: 73–78, 2000.
33.
MostofiF.K., SobinL.H., TosoniI.: Histological typing of urinary bladder tumors. International classification of tumors, No 19. World Health Organization, Geneva, 1973.
34.
KhanN.M., KnappD.W., DenicolaD.B., HarrisR.K.: Expression of cyclooxygenase-2 in transitional cell carcinoma of the urinary bladder in dogs.Am J Vet Res,61: 478–481, 2000.
35.
MohammedS.I., KnappD.W., BostwickD.G., FosterR.S., KhanK.N., MasferrerJ.L., WoernerB.M., SnyderP.W., KokiA.T.: Expression of cyclooxygenase-2 (COX-2) in human invasive transitional cell carcinoma (TCC) of the urinary bladder.Cancer Res,59: 5647–5650, 1999.
36.
PannoneG., BufoP., CaiaffaM.F., SerpicoR., LanzaA., Lo MuzioL., RubiniC., StaibanoS., PetruzziM., De BenedictisM., TursiA., De RosaG., MacchiaL.: Cyclooxygenase-2 expression in oral squamous carcinoma.Int J Immunopathol Pharmacol,17: 273–282, 2004.
37.
KimS.I., KwonS.M., KimY.S., HongS.J.: Association of cyclooxygenase-2 expression with prognosis of stage T1 grade 3 bladder cancer.Urology,60: 816–821, 2002.
38.
ShariatS.F., MatsumotoK., KimJ., AyalaG.E., ZhouJ.H., JianW., BenedictW.F., LernerS.P.: Correlation of cyclooxygenase-2 expression with molecular markers, pathological features and clinical outcome of transitional cell carcinoma of bladder.J Urol,170: 985–989, 2003.
39.
WülfingC., EltzeE., von StruenseeD., WülfingP., HertleL., PiechotaH.: Cyclooxygenase-2 expression in bladder cancer: correlation with poor outcome after chemotherapy.Eur Urol,45: 46–52, 2004.
40.
WheelerM.A., HausladenD.A., YoonJ.H., WeissR.M.: Prostaglandin E2 production and cyclooxygenase-2 induction in human urinary tract infections and bladder cancer.J Urol,168: 1568–1573, 2002.
