Cox-2 gene overexpression in ureteral stump urothelial carcinoma following nephrectomy for renal cell carcinoma: a case report.

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by  Chang, Wei-Pin

Changetal.JournalofMedicalCaseReports2012,6:44
JOURNAL OF MEDICAL
http://www.jmedicalcasereports.com/content/6/1/44
CASE REPORTS
CASE REPORT Open Access
Cox-2 gene overexpression in ureteral stump
urothelial carcinoma following nephrectomy for
renal cell carcinoma: a case report
Wei-Pin Chang1, Tsu-Ming Chien2, Yu-Shiuan Wang3, Siou-Jin Chiu3, Mei-Hui Lee4, Wei-Chiao Chang2,5,
Yii-Her Chou4,6* and Ming-Feng Hou5
Abstract
Introduction: A primary ureteral stump tumor after a nephrectomy is rare; urothelial carcinoma of the ureteral
stump after a nephrectomy for renal cell carcinoma is even rarer. A thorough review of the literature indicated that
only seven cases have previously been reported. In this study, we report the first Taiwanese case of urothelial
carcinoma of the ureteral stump after a nephrectomy. It is also the first female case in the literature. The
relationship between inflammatory genes, medication history and ureteral stump carcinoma after a nephrectomy
for renal cell carcinoma has not been reported.
Case presentation: A 72-year-old Asian Taiwanese women with chronic hepatitis C, liver cirrhosis and chronic
kidney disease underwent a hand-assisted laparoscopic radical nephrectomy in 2001 due to renal cell carcinoma.
Nine years later, she was diagnosed with ureteral stump urothelial carcinoma. Genetic and medication surveys
were performed. Importantly, our patient had taken Chinese herbal drugs for more than 10 years and the
inflammatory gene, Cox-2, was highly expressed in this patient. This is the first report to study the relationship
between the Cox-2 gene and ureteral stump carcinoma after a nephrectomy for renal cell carcinoma.
Conclusion: Long-term multiple use of Chinese herbal drugs could be one of the important risk factors for
developing urothelial cancer. Close functional coupling between Chinese herbal drugs, Cox-2 gene activation and
urothelial cancer should be further investigated.
Introduction Prostaglandins are important inflammatory molecules
The incidence of urothelial carcinoma in the ureter is involved in the pathogenesis of cancer. Prostaglandins
rare, accounting for less than 5% of all urothelial neo- canbemetabolizedfromarachidonicacidbythecycloox-
plasms. It often occurs in the lower third of the ureter ygenases1(Cox-1)andcyclooxygenases2(Cox-2).Cox-1
and the recurrence rate is relatively high [1]. A primary is a constitutive enzyme whereas Cox-2 is an inducible
tumor of the ureteral stump after a nephrectomy is enzyme that is activated by extracellular stimulations
infrequently observed. Moreover, a primary tumor of includingcytokines[9],growthfactors[10]andendotox-
the ureteral stump after a nephrectomy for a renal cell ins [11]. Several lines of evidence indicate that Cox-2 is
carcinoma (RCC) is extremely rare. A thorough review one of the most critical enzymes in tumor metastasis.
of the literature indicated that only seven cases have Cox-2 overexpression may lead to the cancer cell inva-
previously been reported of ureteral stump carcinoma siveness of human breast cancer cells [12]. Clinical stu-
after a nephrectomy for an RCC [2-8]. This eighth dies have extensively documented thatCox-2inhibitors,
observed case is the first reported case in Taiwan. suchasnonsteroidalanti-inflammatorydrugs,canreduce
theincidenceofcoloncancer[13].
Tothebestofourknowledge,therelationshipbetween
inflammatory genes, medication history and ureteral
*Correspondence:[email protected] stump carcinoma after a nephrectomy for an RCC has
4DepartmentofUrology,KaohsiungMedicalUniversityHospital,Taiwan
notbeenreported.Wethereforeconductedaprospective
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study to identify the potential risk factor in the first subsided spontaneously. Cystoscopy revealed whitish
reported case of ureteral stump carcinoma after a debris coating the left ureter orifice; no gross bladder
nephrectomyforanRCCinTaiwan. tumor was seen. A ureter catheter could not be inserted
into her left ureter due to a ureterovesical junction stric-
Case presentation ture. Thus, retrograde pyelography with a cone tip uret-
A72-year-oldAsianTaiwanesewomanwithintermittent, eral catheter was tried, but also failed. However, CT
painless,totalgrosshematuriavisitedtheDepartmentof scans showed a prominent soft tissue mass at the ure-
Urologyofourhospitalin2010.Shehadbeendiagnosed terovesical junction. The middle and lower third parts
withchronichepatitisCandstageIIIchronickidneydis- of her residual left ureter were dilated (Figure 2).
easefor10yearsandhasregularfollow-up.In2001(nine According to the imaging, a urothelial carcinoma of the
years ago), a routine ultrasound examination showed a ureter stump was highly suspected. Therefore, a uretero-
leftrenaltumor.Computedtomography(CT)confirmed scopic examination and biopsy was performed using a
the diagnosis(Figure 1).Shethen was transferredtoour fiberoptic rigid ureteroscope. We tried to use a guide-
Department of Urology and underwent a hand-assisted wire to pass the ureteral orifice cystoscopically but the
laparoscopic radical nephrectomy. The pathological guidewire could only be progressed for less than 1 cm.
reports revealed an RCC of stage T1N1M0, which cov- The ureteroscope was therefore inserted without intra-
eredthecortexandmedullawithcentralareasofnecro- mural dilatation of the ureterovesical junction and it
sis and hemorrhage, measuring 11.0 cm × 7.0 cm × was only possible to examine the ureter up to less than
4.0 cm. The calyx segment of the collecting system was 1 cm from the ureterovesical junction. The biopsy was
alsoincluded.Her ureter wasnotdilatedanditsmucosa thus taken from the lower ureter where it is close to the
was not remarkable. Fortunately, her ureter was free ureterovesical junction. The pathological report showed
from cancer tissues. After the operation, she received a high-grade infiltrating urothelial carcinoma. The
regularfollow-up. tumor invaded the subepithelial connective tissue
At the beginning of 2010, nine years later, our patient (lamina propria) and the pathologic staging of the pri-
had one episode of gross hematuria. The results of mary tumor was T1. A radical operation (ureterectomy
examinations such as urine cytology and cystoscopy with ipsilateral bladder cuff excision or a cystectomy) or
were normal. A CT scan showed two renal stones in her systemic chemotherapy were suggested. Without family
right kidney without other abnormalities. The hematuria support, our patient had been in a depressed state for a
subsided spontaneously. Two months later, another epi- long time. With consideration of the multiple coexisting
sode of gross hematuria occurred. This time, clot forma- systemic diseases, such as liver cirrhosis, chronic kidney
tion was noted in her urine. Once again, the symptoms disease, gallbladder stones, facial palsy, hypertension and
Figure1Axialviewofcontrast-enhancedcomputedtomographyscansrevealingaleftrenaltumor.
Changetal.JournalofMedicalCaseReports2012,6:44 Page3of6
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Figure2Coronalviewofcomputedtomographyscansrevealingaprominentsofttissueattheleftureterovesicaljunction.Themiddle
andlowerthirdpartsofherresidualureterweredilated.
recurrent urinary tract infection, our patient refused influence inflammatory reactions. We therefore com-
both treatment options. She asked for supportive treat- paredgeneexpressionlevelofCox-2betweenthispatient
ment only. andpatientswithcalciumnephrolithiasis.Real-timepoly-
To further identify the possible risk factors contribut- merase chain reactionexperimentsindicatedthata high
ingtotheurothelialcarcinomaoftheureteralstump,we level of expression of the Cox-2 gene was seen in our
checkedthemedicationhistoryofourpatient.Asshown patient with the urothelial carcinoma of the ureteral
in Table 1, our patient had taken several different kinds stump(Figure3).
of drugs for more than 10 years. These were cephalos-
porin, nitroxoline, sulfonamide, levofloxacin for urinary Discussion
tract infection, atenolol, amlodipine, solantin for hyper- An RCC is a common renal parenchymal malignant
tension,atorvastatinforhyperlipidemia,ursodeoxycholic tumor. RCCs originate from the proximal renal tubular
acidforlivercirrhosisandChineseherbaldrugsformul- epithelium in therenalcortex.Urothelialcarcinoma isa
tiple somatic complaints. Importantly, although our commoncanceroftheurinarybladder.Itmayalsooccur
patienthadtakenChineseherbaldrugsformorethan10 in the collecting system of the upper urinary tract, such
years, the compositions of these drugs remain unclear. as the renal pelvis and ureter. The causes of RCCs are
Long-term multiple use of Chinese herbal drugs may unknown; environmental exposure to asbestos, solvents
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Table 1Medication history andthe possible sideeffects
Drug Disease/disturbance Sideeffect
Cefradine Urinarytractinfection Hypersensitivity,elevatedliverenzyme,diarrhea
Nitroxoline Urinarytractinfection Gastrointestinalintolerance,urinecoloration
Sulfonamide Urinarytractinfection Hypersensitivity,folicaciddeficiency,hematologicalabnormality
Levofloxacin Urinarytractinfection Diarrhea,tendinitis,seizureneuropathy,elevatedliverenzyme
Atenolol Hypertension Bradycardia,cough,Raynaud’ssyndrome
Amlodipine Hypertension Flush,tachycardia,edema
Solantin Thromboembolism Dizziness,abdomendistress,angina,headache
Ursodeoxycholicacid Livercirrhosis Gastrointestinaldisturbance
Atorvastatin Hyperlipidemia Gastrointestinaldisturbance,elevatedliverenzyme,myopathy,neuropathy
Chineseherbdrugs Multiplesomaticcomplaints Unknown
andcadmium, smoking and genetic mutation have been A primary ureteral stump tumor can be defined as a
implicated.Thecausesofurothelialcancerincludesmok- tumor occurring in the closed ureteral stump after a
ing and occupational exposure to chemicals, dyes, rub- nephrectomy for either benign or malignant disease
bers, petroleum, leathers and printing materials; people other than a urothelial tumor. Clinically, both diagnoses
who are exposed to these for a long time are a high-risk and treatments for a ureteral stump tumor are still elu-
groupfordevelopingurothelialcancers.Geneticchanges sive. Furthermore, a primary urothelial carcinoma of the
mayalsooccurthroughouttheurothelium. ureteral stump after a nephrectomy for an RCC is
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Patients` No. 1 2 3
Figure3TheCox-2geneexpressionlevelwascheckedinpatientswithcalciumnephrolithiasis(patients1and2)orwithaurothelial
carcinomaoftheureteralstump(patient3).
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extremely rare. Only seven cases were reported in the beassociatedwiththepathogenesisoftheprimaryureteral
literature (Table 2). Our case is the first case in Taiwan stumptumor.TheCox-2genecanbeevokedbyavariety
and is the first female case in the literature. ofchemicalcompounds,includingalkaloids,polysacchar-
In the reported cases, the mean interval between the ides and heavy metals. Chinese herbal drugs contain a
nephrectomy and detection of the ureteral stump large amount of alkaloids, polysaccharides and heavy
tumor was 7.1 ± 7.0 years, ranging from 0.9 years to 23 metals.Long-termuseofChineseherbaldrugsmayresult
years. In a report by Kim et al., the interval between inphysiologicaldysfunction.AnotherpostulationbyKlee
the detection of a ureteral stump tumor and the and colleagues [5] was that a prior bladder carcinoma
nephrectomy for benign renal disease was 76.5 months could make reflux implantation into the ureteral stump
[14]. Although the etiology of a ureteral stump tumor more likely, even though no significant vesicoureteral
remains to be seen, metaplastic changes caused by reflux was noted. In other words, a history of previous
chronic inflammation due to infection or stone irrita- cancerelsewhere intheurinarytractwasthoughttobea
tion, malignant metamorphosis caused by leukoplakia high risk factor for ureteral stump cancer. Unlike the
[15], exposure to carcinogenic substances, a high risk assumption proposedbyKleeandcolleges, thepatientin
of genetic cancer susceptibility and several others fac- ourcasehadnohistoryofbladdercancer,butherureteral
tors are very likely to be associated with this rare dis- stumphadpossibly beenexposedtourinary carcinogens
ease. Chronic inflammation is often related to formorethan10yearsbecauseofvesicoureteralreflux.
squamous cell metaplasia resulting in squamous cell
carcinoma [16]. After a nephrectomy, the ureteral Conclusions
stump is no longer exposed to the chemical carcino- Urothelial carcinoma of the ureteral stump after a
gens which are present in the urine; resulting in a low nephrectomy for an RCC is rare. A ureteral excision
possibility of developing cancer from a urinary carcino- made duringa nephrectomy shouldbe aslarge aspossi-
gen. Genetic hypersensitivity, mutation or pharmacolo- ble for benign disease or a non-urothelial tumor. If the
gical carcinogenetic effects provide other possibilities ureter is left after the nephrectomy, the ureteral stump
for cancer development. Our patient had experienced should be evaluated and followed-up carefully. Long-
chronic recurrent urinary tract infection, with episodes term multiple use of Chinese herbal drugs could be one
occurring three to four times every year. Several of the important risk factors for developing urothelial
reports have indicated the correlation between Chinese cancer. Close functional coupling between Chinese her-
herbal drugs and urothelial carcinoma [17-20]. A bal drugs, Cox-2 gene activation and urothelial cancer
patient with liver cirrhosis, such as ours, may have a shouldbefurtherinvestigated.
reduced ability to metabolize herbal drugs due to
damage to the liver. Therefore, the side effects of Chi- Consent
nese herbal drugs may be amplified and accumulate. Oral and written informed consent was obtained from
In addition to chemical carcinogenesis from Chinese the patient and her next-of-kin for publication of this
herbaldrugs,geneticeffectsmightcontributetomalignant case report and any accompanying images. A copy of
tumors.Cox-2polymorphismhasbeenshowntobeapre- the written consent is available for review by the Editor-
dictive marker of survival in non-small cell lung cancer in-Chief of this journal.
patientstreated with chemoradiotherapyorradiotherapy
[19,21,22]. Our results, consistent with previous reports,
indicatedthat a highlevel ofCox-2 gene expression may Acknowledgements
ThisstudywassupportedbyfundingfromanExcellenceforCancer
ResearchCentergrant,DepartmentofHealth,ExecutiveYuan,Taiwan,R.O.C.
(DOH101-TD-C-111-002).
Table 2Patient data foraureteral stumptumor after a
Authordetails
nephrectomy forarenal cellcarcinoma
1DepartmentofHealthcareManagement,YuanpeiUniversity,HsinChu,
Case Age Sex Interval Side Reference Taiwan.2SchoolofPost-baccalaureateMedicine,KaohsiungMedical
(years) University,Taiwan.3DepartmentofMedicalGenetics,KaohsiungMedical
University,Taiwan.4DepartmentofUrology,KaohsiungMedicalUniversity
1 75 M Twoandahalf Right [4]
Hospital,Taiwan.5Cancercenter,KaohsiungMedicalUniversityHospital,
2 62 M Twoandahalf Right [5] Kaohsiung,Taiwan.6DepartmentofUrology,KaohsiungMedicalUniversity,
3 70 M Seven Right [3] Taiwan.
4 49 M 23 Left [2]
Authors’contributions
5 88 M Six Left [6] WPCdraftedthearticle.WPC,TMCandYSWanalyzedandinterpretedthe
6 64 M Six Right [8] patientdata.MHLphotographedandinterpretedthepathologicfindings.
WCC,MFH,WPCandSJCtookpartinthecriticalrevisionandYHCtookpart
7 68 M 0.9 Right [7]
inthediagnosis,treatmentofthepatientandgavefinalapprovalofthe
8 72 F Nine Left Presentcase manuscript.Allauthorshavemadesubstantiveintellectualcontributionsto
Changetal.JournalofMedicalCaseReports2012,6:44 Page6of6
http://www.jmedicalcasereports.com/content/6/1/44
thisstudyandtothemanuscriptandhavereadandapprovedthefinal 20. ShumS:Chineseherbsandurothelialcarcinoma.NEnglJMed2000,
manuscript. 342:1686-1692.
21. BiN,YangM,ZhangL,ChenX,JiW,OuG,LinD,WangL:
Competinginterests Cyclooxygenase-2geneticvariantsareassociatedwithsurvivalin
Theauthorsdeclarethattheyhavenocompetinginterests. unresectablelocallyadvancednon-smallcelllungcancer.ClinCancerRes
2010,16:2383-2390.
Received:26October2011 Accepted:30January2012 22. GrimmingerPP,StöhlmacherJ,VallböhmerD,SchneiderPM,HölscherAH,
Published:30January2012 MetzgerR,DanenbergPV,BrabenderJ:Prognosticsignificanceand
clinicopathologicalassociationsofCOX-2SNPinpatientswithnonsmall
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