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Cox-2 gene overexpression in ureteral stump urothelial carcinoma following nephrectomy for renal cell carcinoma: a case report
© Chang et al; licensee BioMed Central Ltd. 2012
Received: 26 October 2011
Accepted: 30 January 2012
Published: 30 January 2012
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.
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.
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.
The incidence of urothelial carcinoma in the ureter is rare, accounting for less than 5% of all urothelial neoplasms. It often occurs in the lower third of the ureter and the recurrence rate is relatively high . A primary tumor of the ureteral stump after a nephrectomy is infrequently observed. Moreover, a primary tumor of the ureteral stump after a nephrectomy for a renal cell carcinoma (RCC) is extremely rare. A thorough review of the literature indicated that only seven cases have previously been reported of ureteral stump carcinoma after a nephrectomy for an RCC [2–8]. This eighth observed case is the first reported case in Taiwan.
Prostaglandins are important inflammatory molecules involved in the pathogenesis of cancer. Prostaglandins can be metabolized from arachidonic acid by the cyclooxygenases 1 (Cox-1) and cyclooxygenases 2 (Cox-2). Cox-1 is a constitutive enzyme whereas Cox-2 is an inducible enzyme that is activated by extracellular stimulations including cytokines , growth factors  and endotoxins . Several lines of evidence indicate that Cox-2 is one of the most critical enzymes in tumor metastasis. Cox-2 overexpression may lead to the cancer cell invasiveness of human breast cancer cells . Clinical studies have extensively documented that Cox-2 inhibitors, such as nonsteroidal anti-inflammatory drugs, can reduce the incidence of colon cancer .
To the best of our knowledge, the relationship between inflammatory genes, medication history and ureteral stump carcinoma after a nephrectomy for an RCC has not been reported. We therefore conducted a prospective study to identify the potential risk factor in the first reported case of ureteral stump carcinoma after a nephrectomy for an RCC in Taiwan.
Medication history and the possible side effects
Urinary tract infection
Hypersensitivity, elevated liver enzyme, diarrhea
Urinary tract infection
Gastrointestinal intolerance, urine coloration
Urinary tract infection
Hypersensitivity, folic acid deficiency, hematological abnormality
Urinary tract infection
Diarrhea, tendinitis, seizure neuropathy, elevated liver enzyme
Bradycardia, cough, Raynaud's syndrome
Flush, tachycardia, edema
Dizziness, abdomen distress, angina, headache
Gastrointestinal disturbance, elevated liver enzyme, myopathy, neuropathy
Chinese herb drugs
Multiple somatic complaints
An RCC is a common renal parenchymal malignant tumor. RCCs originate from the proximal renal tubular epithelium in the renal cortex. Urothelial carcinoma is a common cancer of the urinary bladder. It may also occur in the collecting system of the upper urinary tract, such as the renal pelvis and ureter. The causes of RCCs are unknown; environmental exposure to asbestos, solvents and cadmium, smoking and genetic mutation have been implicated. The causes of urothelial cancer include smoking and occupational exposure to chemicals, dyes, rubbers, petroleum, leathers and printing materials; people who are exposed to these for a long time are a high-risk group for developing urothelial cancers. Genetic changes may also occur throughout the urothelium.
In the reported cases, the mean interval between the nephrectomy and detection of the ureteral stump tumor was 7.1 ± 7.0 years, ranging from 0.9 years to 23 years. In a report by Kim et al., the interval between the detection of a ureteral stump tumor and the nephrectomy for benign renal disease was 76.5 months . Although the etiology of a ureteral stump tumor remains to be seen, metaplastic changes caused by chronic inflammation due to infection or stone irritation, malignant metamorphosis caused by leukoplakia , exposure to carcinogenic substances, a high risk of genetic cancer susceptibility and several others factors are very likely to be associated with this rare disease. Chronic inflammation is often related to squamous cell metaplasia resulting in squamous cell carcinoma . After a nephrectomy, the ureteral stump is no longer exposed to the chemical carcinogens which are present in the urine; resulting in a low possibility of developing cancer from a urinary carcinogen. Genetic hypersensitivity, mutation or pharmacological carcinogenetic effects provide other possibilities for cancer development. Our patient had experienced chronic recurrent urinary tract infection, with episodes occurring three to four times every year. Several reports have indicated the correlation between Chinese herbal drugs and urothelial carcinoma [17–20]. A patient with liver cirrhosis, such as ours, may have a reduced ability to metabolize herbal drugs due to damage to the liver. Therefore, the side effects of Chinese herbal drugs may be amplified and accumulate.
In addition to chemical carcinogenesis from Chinese herbal drugs, genetic effects might contribute to malignant tumors. Cox-2 polymorphism has been shown to be a predictive marker of survival in non-small cell lung cancer patients treated with chemoradiotherapy or radiotherapy [19, 21, 22]. Our results, consistent with previous reports, indicated that a high level of Cox-2 gene expression may be associated with the pathogenesis of the primary ureteral stump tumor. The Cox-2 gene can be evoked by a variety of chemical compounds, including alkaloids, polysaccharides and heavy metals. Chinese herbal drugs contain a large amount of alkaloids, polysaccharides and heavy metals. Long-term use of Chinese herbal drugs may result in physiological dysfunction. Another postulation by Klee and colleagues  was that a prior bladder carcinoma could make reflux implantation into the ureteral stump more likely, even though no significant vesicoureteral reflux was noted. In other words, a history of previous cancer elsewhere in the urinary tract was thought to be a high risk factor for ureteral stump cancer. Unlike the assumption proposed by Klee and colleges, the patient in our case had no history of bladder cancer, but her ureteral stump had possibly been exposed to urinary carcinogens for more than 10 years because of vesicoureteral reflux.
Urothelial carcinoma of the ureteral stump after a nephrectomy for an RCC is rare. A ureteral excision made during a nephrectomy should be as large as possible for benign disease or a non-urothelial tumor. If the ureter is left after the nephrectomy, the ureteral stump should be evaluated and followed-up carefully. 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.
Oral and written informed consent was obtained from the patient and her next-of-kin for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
This study was supported by funding from an Excellence for Cancer Research Center grant, Department of Health, Executive Yuan, Taiwan, R.O.C. (DOH101-TD-C-111-002).
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