|Year : 2009 | Volume
| Issue : 3 | Page : 505-512
|Post kidney transplant transitional cell carcinoma of bladder
Mohammed Al Ghonaim, Habib-ur-Rahman, Abdulkareem Al Suwaida, Akram Askar, Salman Imtiaz, Jamal S Al-Wakeel
Section of Nephrology, Department of Medicine, King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia
Click here for correspondence address and email
Keywords: Kidney transplant, Malignancy, Immunosuppression, Transitional cell carcinoma
|How to cite this article:|
Al Ghonaim M, Hu, Al Suwaida A, Askar A, Imtiaz S, Al-Wakeel JS. Post kidney transplant transitional cell carcinoma of bladder. Saudi J Kidney Dis Transpl 2009;20:505-12
|How to cite this URL:|
Al Ghonaim M, Hu, Al Suwaida A, Askar A, Imtiaz S, Al-Wakeel JS. Post kidney transplant transitional cell carcinoma of bladder. Saudi J Kidney Dis Transpl [serial online] 2009 [cited 2020 Jun 6];20:505-12. Available from: http://www.sjkdt.org/text.asp?2009/20/3/505/50794
| Introduction|| |
Kidney transplant is the best way of treating the end stage renal disease patients, but prolonged and heavy immunosuppressive therapy expose them for other complications, one of them is the increase risk of malignancy. , The mechanism which causes the increase susceptibility to malignancies includes decrease immune surveillance, increased oncogenic virus load and a direct neoplastic effect of the drug them selves. 
The incidence of some of the tumors are high as much as 3-5 fold in transplant patient as compared to age matched general population and it also shows wide geographical variations in incidence. 
Transitional cell carcinoma (TCC) is also encountered in post transplant recipients, although it is not a common tumor after transplant. The incidence is 2% of all de novo tumors in organ allograft recipients in Cincinnati transplant tumor registry (C.T.T.R). There is predilection or male preponderance and it occurs in fifth or sixth decade of life. The incidence is high in some subset of patients like the patient with the history of analgesic nephropathy,  and long standing use of underground water ingestion with high arsenic level,  (as in Taiwan where transitional cell carcinoma is high in general population,)  and the use of Chinese herbs leading to the ESRD [Table 1].  Transitional cell carcinoma presents mostly with frank hematuria, microscopic hematuria, recurrent urinary tract infection and urinary tract obstruction.
| Case Report|| |
We are reporting a case of 56 year old Saudi male who works as messenger in the university office. He was diagnosed to have ESRD secondary to Schistosomiasis more than 15 years ago. He had high blood pressure of the same duration. He is ex-smoker quitted smoking 20 years ago and he smoked for 15 years averaged 2 packs per day. There is no history of long standing analgesic abuse. He was started hemodialysis. After 2 years of hemodialysis he had his first kidney transplant through unrelated donor and this graft survived for 2 years and came back on hemodialysis due to chronic allograft nephropathy. He remained on hemodialysis for 10 years and had a second transplant through unrelated donor 2 years ago. The graft was stable and well functioning. Since last one year he had recurrent urinary tract infection. Patient visited the clinic as scheduled follow up, complained of left flank pain. On examination; Vitals stable with the temperature of 36.6°C and blood pressure 130/80 mmHg. Graft was non tender. Labs showed WBC count 3.7 × 10 9 /L, Hb 12 g/L, Plt 271 × 10 9 /L. Biochemistry showed BUN 10 mmol/L, creatinine 107 µmol/L, Na 138 mmol/L, K 4.6 mmol/L, LFT Normal. Urine examination was unremarkable. Ultrasound showed a moderately hydronephrotic graft and MRI of abdomen showed thickening of the posteriolateral region of the urinary bladder along with the three masses surrounding the graft [Figure 1]. DTPA scan ruled out obstructive uropathy [Figure 2]. The urinary cytology was normal and showed no malignant cells. Tumor markers CEA, AFP, PSA and CA 19.9 all were within normal limits. Schistosoma serology was negative.
The cystoscopy and biopsy showed a highly malignant transitional cell carcinoma invading up to the muscularis propria (PT2bN3M0) [Figure 3] and [Figure 4]. There was no metastasis on further screening.
He was on cyclosporine 50 mg twice daily, mycophenolate (MMF) 500 mg twice daily and Prednisone 5 mg daily. He was started on Cisplatin based chemotherapy after reduction in immunosuppressive therapy by discontinuation of MMF. After receiving of the 6 th session of the chemotherapy he was re-evaluated by MRI which showed the regression of the tumor and the peripheral three masses surrounding the graft [Figure 5]. The course of the chemotherapy remained uneventful, except on one occasion he developed decrease in white blood cells count which responded well the colony stimulating factor.
| Discussion|| |
Transitional cell carcinoma is a rare tumor in kidney transplant patients and data from the Arab world (Syria, Jordan, Egypt, and Saudi Arabia) verifies it. Transplant recipients with immunosuppressive therapy are at high risk of developing malignancies.  Many mechanisms have been proposed to explain the high incidence of post-transplantation neoplasm include, impairment of the immune surveillance mechanism, an increased susceptibility to oncogenic virus. Lymphoproliferation as a defective feedback mechanism and uremia per se as a predisposing factor for cancer development.
Post kidney transplant incidence of transitional cell carcinoma
Israel Penn International Transplant Tumor Registry; (IPITTR), TCC of bladder comprised 0.87% of reported malignancies. United Network for Organ Sharing; (UNOS), 5 cases of TCC out of 6288 transplants that is 0.08%.
Transitional cell carcinoma is the most common type of cancer in the one study group in Taiwan  and represents 42% (24/55) of post transplant malignancies [Figure 6].
| Diagnosis|| |
- Microscopic cytology of urinary sediment or saline bladder wash to detect malignant cells (saline bladder washes more accurate).
- Microscopic cytology is more sensitive in high grade tumors or carcinoma in situ but can be falsely negative in 20% of cases.
Newer tests for screening of bladder cancer
- Hyaluronic acid (Hyaluronidase activity)
- Nuclear Matrix protein (NMP) especially BLCA-4
- Telomerase activity in urine. Several studies have shown an overall sensitivity and specificity of 66% (range 47% to 89%) and of 75% (range 60% to 84%), respectively, for the NMP22 assay ,,,,,,,,,,
- Standard procedure for diagnosis and staging -cystosocpy and bimanual examination under anesthesia (EUA) before and after resection.
AJCC stage subgroups
- Stage 0: Ta, or Tis, N0, Mo
- Stage I: T1, N0, M0
- Stage II: T2a or T2b, N0, M0
- Stage III: T3a or T3ba or T4a, N0, MO
- Stage IV: T4b, N0, M0 or Any T with N1 to N3 with M0 or Any T, any N, with M1
Protocol for screening of patients after transplantation
History and physical examination to exclude disseminated or localized organ involvement by malignancy (every 3 months during the first year after transplantation, subsequently at yearly intervals)
Ultrasonography or CT scan of the native kidney (at yearly intervals)
In selected cases, PSA and digital rectal examination (male > 50 yr, at yearly intervals), fecal occult blood testing (age > 50 yr, at yearly intervals), abdominal ultrasound and serum afetoprotein levels (in carriers of hepatitis B or C virus), cystoscopy (de novo hematuria, particularly when history of cyclophosphamide treatment or schistosomiasis) according to Kasiske et al and others. 
| Treatment|| |
For the purpose of treatment, transitional cell carcinoma can be grouped in to three major types: (1) superficial, (2) muscle invasive and (3) metastatic
Superficial bladder Ca
- 80% of all bladder carcinoma
Aims of treatment are to eradicate the primary lesion, to prevent superficial relapse, to prevent progression to muscle invasive and less curable form of disease. Initial management is complete transurethral resection.
Depending upon cystoscopic and pathological findings, superficial bladder cancers can be further sub divided in low risk group and high risk group.
Further management of low risk: Periodic cystoscopic examination and urine cytology every 6 month for 2 years and yearly for at least 5 years. Recurrence and progression are managed by transurethral resection.
Bladder tumor antigen (BTA) and nuclear matrix protein (NM22) in voided urine as supplement to cystoscopic and cytological evaluation.
Further management of high-risk: intravesical chemotherapy.
Intravesical chemotherapeutic agents:
Bacillus Calmette-Guerin (BCG) is agent of choice. Combination of intravesical BCG and subcutaneous BCG is better. Cystectomy for patients after 2 nd failure.
Immediate single Mitomycin-C instillation: prolongs recurrence free survival.
Follow up for high risk group
Cystoscopy and cytology 3 monthly for year 1, 6 monthly for next 5 yrs and yearly after.
Muscle Invasive Bladder Cancer
15% of all bladder cancers. Stage II and III of AJCC staging. Aim of treatment for muscle invasive disease is to cure the patient and to determine which modality of treatment is best for a particular patient. Divided into bladder sparing and non bladder sparing modalities.
Bladder Sparing Modalities
Transurethral Resection alone in few superficial solitary muscle invasive diseases (T2a) in one muscle invasive tumor without carcinoma in situ (CIS) or dysplasia, tumor located at dome or posterior wall and at least 2 cm available surgical margin. Radiotherapy as definitive treatment: Total dose 5000-7000 Gy. Complete response in 40% to 50%. 5 year survival rate: 30%-40%. Local recurrence major problem (25% of deaths)
Bladder preservation using concurrent or sequential chemo radiotherapy
Transurethral bladder tumor resection (TURBT) and chemotherapy provides durable local control in less than 20% of patients. Radiation alone is not sufficient. Cisplatin and 5FU are capable of radio-sensitization of tumor tissue. 50% of muscle invasive disease harbor occult metastasis.
Non-Bladder Sparing Modalities
Radical cystectomy standard treatment. Local control rates at 5 and 10 years are > 90% and 88%. 5 year survival rate: 40 to 60%. Pre operative radiotherapy 4000 Gy followed by surgery has shown benefit in prolonging survival. No survival benefit from post cystectomy, single agent or multidrug agent adjuvant chemotherapy.
Standard indications for radical cystectomy
Muscle - invading tumors unsuitable for segmental resection. (1) Low stage tumor unsuitable for conservative management due to multicentricity, (2) Frequent recurrences resistant to in-travesical instillation, (3) High grade tumor associated with Tis orBladder symptoms, such as frequency or haemorrhage-"bladder cripple".
Treatment of metastatic bladder cancer
Choosing the most effective palliation. Systemic chemotherapy is the only option for metastatic bladder cancer. Despite good response, disease continues to recur and long term survival is rare. Single agent chemotherapy: Complete response is uncommon. Responses last for about 3 to 4 months. Cisplatin administered every 3 to 4 weeks and methotrexate in the weekly or biweekly schedule has given pooled response rate of 30% and 29% respectively
Most accepted modality for metastatic bladder cancer:
CISCA regimen: (Cisplatin, cyclophosphamide, adriamycin) 70% response rate, complete in 39%. CMV regimen: (Cisplatin, methotrexate, vinblastine) 28% complete and partial response. MVAC regimen: (Methotrexate, vinblastine, adriamycin, cisplatin) Most popular regimen (response rate: 40- 70% and 25-30% complete response. Randomized trial comparing MVAC with cisplatin and MVAC with CISCA revealed that MVAC is superior. Long term follow up five year survival of 32% (nodal disease) and 17% (advanced metastatic diseases).
Current front line chemotherapy for metastatic bladder cancer remains MVAC and CMV. MVAC regimens has produced better response rates and survival than single agent cisplatin or CISCA.
| Prognosis|| |
- TCC in Renal transplant patient's poses special problems and challenges for urologists.
- Clinical course of tumor metastasis is rapid and aggressive
- Early diagnosis can be done by careful investigation of any episode of hematuria
The prognosis of noninvasive TCC in RTx recipients is good. The risk factor which includes male gender, cigarette smoking and schistosomiasis were present in our patient and analgesic intake, exposure to the hydrocarbon and underground water intake was absent. The presentation was also atypical, he did not have the frank hematuria but he had the history of recurrent urinary tract infections. His graft was moderately hydronephrotic since transplantation and he had good urinary output and stable graft function, follow up ultrasounds didn't show any increase in the degree of hydronephrosis.
F-15 DTPA showed a good clearance of the graft. He had the history of schistosomiasis which was the primary cause of his renal failure in fact when the bladder histopathology was evaluated, it revealed schistosomiasis ova in the tissue, but squamous cell carcinoma is mostly associated with the schistosomiasis not the transitional cell carcinoma.  The nature of the tumor was aggressive and it was PT2bN3M0. At the time of his first presentation which correlated with the other reported series. He was subjected to cisplatin based chemotherapy which is standard therapy at this stage of tumor. After the completion of 6 th cycle his follow up shows remarkable reduction in the tumor load.
| Conclusion|| |
Transitional cell carcinoma is a rare tumor after transplantation except in some populations where it is rapidly progressive but responds well after decreasing immunosuppressive medicine and Cisplatin based chemotherapy. He is the first case report of transitional cell carcinoma from Saudi Arabia after 2 nd renal transplantation. It was on presentation multifocal tumor without distant metastasis.
| Questions and Answers|| |
Dr. Akram Askar (Chairman of RNTC): The floor is now open for discussion.
Prof. Jamal Al-Wakeel (King Khalid University Hospital): There is any published data about similar cases reported from Saudi Arabia or Arabic countries?
Speaker (Dr. Habib-ur-Rahman, King Khalid University Hospital): As I know, this is the first case reported after second renal transplant, transitional cell carcinoma of the bladder in Saudi Arabia. Also, it is known to be a very rare tumor, according to the UNOS registry the incidence of TCC is 0.08% only.
Prof. Al-Wakeel: May be Dr. Faissal Shaheen (Director of SCOT) could comment on this based on the national registry of renal transplantation.
Dr. Shaheen: Over more than 1,600 cases of deceased renal transplantation performed in Saudi Arabia, this is maybe the first documented case of post renal transplant TCC.
Prof. Al-Wakeel: My second question about the management decision, why you decided to reduce the immunosuppressive treatment only and not to apply a more agressive plan? Since your patient with multiple tumors and and the size is more than 5 cm.
Speaker: There is no established consensus for the management of this rare presentation, however most of the published data indicate that the use of immunosuppresive treatment as cyclosporine increases tumor incidence after transplantation. So we did a logic plan by eliminating the MMF and applying a chemotherapy with satisfied outcome.
Dr. Sabry (Prince Salman Kidney Disease Center): Since your patient with history of schistosomiasis and previous renal tx, my question is a cystoscopy was done as pretransplant work-up? And what was the finding? My second question is about the risk factor of immunosuppression in TCC, is it related to over-all immunosuppression level or related to specific agent? And do you consider to change the type of immunosuppressive drug by using rapamycin for example to get benefit of antiproliferative action?
Speaker: Yes, a cystoscopy was done before the second transplantation and was normal, also a preventive treatment for schistosomia has been given to the patient. To answer the second question, we know that the new agent as sirolimus and rapamycin have antiproliferative effect an it reduces the tumor proliferation and improve the graft survival with reduction of risk for malignancy post tx. However, several study and mainly from Taiwan proved that the decrease of the immunosuppressive therapy is the standard procedure to be done with good outcome in tumor regression.
Prof. Al-Wakeel: Do you have any explanation for the high incidence of TCC in Taiwan? And could this be related to the high prevalence of schistosomiasis or there are other factors?
Speaker: The explanation of high incidence of TCC in general population in Taiwan could be related to the high arsenic level of underground water, the analgesic abuse, and the use of chinese herbs.
Question from the Audience: Do you have any data about TCC in patient with ESRD and anuria without transplant?
Speaker: To my knowledge there is no data about TCC in ESRD anuric patients not receiving immunosuppressive drugs.
Dr. Askar: Thank you everybody for your attendance
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Jamal S Al-Wakeel
Department of Medicine, King Saud University, Riyadh
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
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