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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2009  |  Volume : 20  |  Issue : 3  |  Page : 505-512
Post kidney transplant transitional cell carcinoma of bladder


Section of Nephrology, Department of Medicine, King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia

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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 Top


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. [1],[2] 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. [3]

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. [4]

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, [5] and long standing use of underground water ingestion with high arsenic level, [6] (as in Taiwan where transitional cell carcinoma is high in general population,) [7] and the use of Chinese herbs lea­ding to the ESRD [Table 1]. [8] Transitional cell carcinoma presents mostly with frank hema­turia, microscopic hematuria, recurrent urinary tract infection and urinary tract obstruction.


   Case Report Top


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 Top


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. [10] 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 [9] and represents 42% (24/55) of post transplant malignancies [Figure 6].


   Diagnosis Top


Cytology

  • 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 [11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21]


Cystoscopy

  • 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. [22]


   Treatment Top


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

Combination chemotherapy

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 Top


  • 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. [8] 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 Top


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.[24]


   Questions and Answers Top


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

 
   References Top

1.Birkeland SA, Lokkegaard H, Storm HH. Cancer risk in patients on Dialysis and after renal transplantation. Lancet 2000;35:1886-7.   Back to cited text no. 1    
2.Gaya SB, Rees AJ, Lechler RI, William G, Matoes PD. Malignant disease in patients with long term renal transplants. Transplantation 1995;59:1705-9.  Back to cited text no. 2    
3.Pen I. De Novo cancers in organ allograft recipients. Curr Opin Organan Transplant 1998;3:188-96.  Back to cited text no. 3    
4.Swindle P, Falk M, Rigby R, Patric J, Haveley C, Nicol D. Transitional cell carcinoma in renal transplant recipients: The influence of compound analgesics. Br J Urol 1998;81:229­-33.  Back to cited text no. 4    
5.Liao CH, Chuch SC, Lai MK, Chen J. Transitional cell carcinoma in renal transplant recipients. Transplant Proc 2004;36:2152-3.  Back to cited text no. 5    
6.Chiou HY, Chiou ST, Hsu YH, et al. Incidence of transitional cell carcinoma and arsenic in drinking water. A follow up study 8102 resident in an arsenic endemic area in Northeastern Taiwan. Am J Epidemiol 2001;153:411-8.  Back to cited text no. 6    
7.Li XB, Xing NZ, Wang Y, Hu XP, Yin H, Zhang XD. Transitional cell carcinoma in renal transplant recipients, A single Centre expe­rience. Int J Urol 2008;15(1):53-7.  Back to cited text no. 7    
8.Mill RD, Turner WH. Tumours of Bladder. In: Davison AM, Cameron JS, Grunfeld JP, et al, (eds): Oxford Textbook of Clinical Nephrology, 3rd ed. Oxford, UK, Oxford University Press, 2005, pp 2549.  Back to cited text no. 8    
9.Kao YL, Ou YC, Yang CR, Ho HC, Su Ck, Shu KH. Transitional cell carcinoma in renal transplant recipients. World J Surg 2003;27(8): 912-6.  Back to cited text no. 9    
10.Dantal J, Pohanka E. Malignancies in renal transplantation: An unmet medical need. Nephrol Dial Transplant 2007;22(supp 1):i4-10.  Back to cited text no. 10    
11.Ramakumar S, Bhuiyan J, Besse JA, Roberts SG, Wollan P C, Blute M L, O'Kane D J, "Compa­rison of screening methods in the detection of bladder cancer". J Urol 1999;16:388-94.  Back to cited text no. 11    
12.Wiener H G, Mian C, Haitel A, Pycha A, Schatzl G, Marberger M, "Can urine bound diagnostic tests replace cystoscopy in the management of bladder cancer?". J Urol 1998;159:1876-80.  Back to cited text no. 12    
13.Sarosdy M F, Hudson M A et al., "Improved detection of recurrent bladder cancer using the Bard BTA stat Test". Urology 1997;50:349-53.  Back to cited text no. 13    
14.Lekili M, Sener E, Demir M A, Temeltas G, Muezzinoglu T, Buykusu C, "Comparison of the nuclear matrix protein 22 with voided urine cytology in the diagnosis of transitional cell carcinoma of the bladder". Urol Res 2004;32: 124-8.  Back to cited text no. 14    
15.Lahme S, Bichler K H, Feil G, Krause S, "Comparison of cytology and nuclear matrix protein 22 for the detection and follow-up of bladder cancer". Urol Int 2001;66:72-7.  Back to cited text no. 15    
16.Giannopoulos A, Manousakas T, Gounari A, Constantinides C, Choremi-Papadopoulou H, Dimopoulos C, "Comparative evaluation of the diagnostic performance of the BTA stat test, NMP 22 and urinary bladder cancer antigen for primary and recur-rent bladder tumours". J Urol 200;2:470-5.  Back to cited text no. 16    
17.Ponsky L E, Sharma S, Pandrangi L, Kedia S, Nelson D, Agarwal A, Zippe C D, "Screening and monitoring for bladder cancer: refining the use of NMP22". J Urol 2001;1:75-8.  Back to cited text no. 17    
18.Hughes J H, Katz R L, Rodriguez-Villanueva J, Kidd L, Dinney C, Grossman H B, Fritsche H A Jr, "Urinary nuclear matrix protein 22 (NMP22): a diagnostic adjunct to urine cyto­logic examination for the detection of recurrent transitionalcell carcinoma of the bladder". Diagn Cytopathol 1999;20:285-90.  Back to cited text no. 18    
19.Stampfer D S, Carpinito G A, Rodriquez­Villanueva J et al., "Evaluation of NMP 22 in the detection of transitional cell carcinoma of the bladder". J Urol 1998;159:394-8.  Back to cited text no. 19    
20.Witjes J A, van der Poel H G, van Balken M R, Debruyne F M, Schalken J A, "Urinary NMP22 and karyometry in the diagnosis and follow-up of patients with superficial bladder cancer". Eur Urol 1998;33(4):387-91.  Back to cited text no. 20    
21.Landman J, Chang Y, Kavaler E, Droller M J, Liu C S, "Sensitivity and specificity of NMP­22, telomerase, and BTA in the detection of human bladder cancer". J Urol 1998;52:398­402.  Back to cited text no. 21    
22.Miyanaga N, Akaza H, Ishikawa S et al., "Clinical evaluation of nuclear matrix protein 22 (NMP22) in urine as a novel marker for urothelial cancer". Eur Urol 1997;31:163-8.  Back to cited text no. 22    
23.Morath C, Mueller M, Golschmidt H et al. Malignancies in renal transplantation. J Am Soc Nephrol 2004;15:1582-8.  Back to cited text no. 23    
24.Shaaban A. Incidence and types of malignant tumors in renal transplant recipients: A single center experience. Saudi J Kidney Dis Transplant 1998; 9(2):105-9.  Back to cited text no. 24    

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Correspondence Address:
Jamal S Al-Wakeel
Department of Medicine, King Saud University, Riyadh
Saudi Arabia
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PMID: 19414965

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