Synchronous RCC and TCC of the Kidney in a Patient with Multiple Recurrent Bladder Tumors

Case Review

CASE REVIEW Bladder Tumors Synchronous RCC and TCC of the Kidney in a Patient With Multiple Recurrent Bladder Tumors Kiarash Michel, MD, and Arie Belldegrun, MD UCLA School of Medicine Los Angeles Development of concomitant renal TCC and RCC is an uncommon occurrence, yet many interesting issues can be addressed with this model. The possibility of misdiagnosing a renal TCC for an RCC, the options and importance of treating a retained ureteral stump after performing a radical nephrectomy for a renal TCC, and the risk of developing lower tract TCC in patients with upper tract TCC are some of the issues raised in this case review. [Rev Urol 1(2):99-103, 1999] Key words: Cancer, renal • Cancer, bladder • Nephrectomy • BCG therapy r. S, a 74-year-old attorney, presented to his primary urologist with an episode of gross hematuria. He denied any history of trauma, flank pain, fever, or past history of stones. His past medical history included hypertension and bladder outlet obstructive symptoms, which were treated with hydrochlorothiazide (HydroDIURIL®) and terazosin (Hytrin®). Past surgical history and family history were noncontributory. On physical examination, Mr. S was an obese elderly male who was otherwise in good physical condition. He was afebrile and normotensive. No tachycardia was noted. He had no palpable abdominal masses and no costovertebral tenderness or suprapubic mass. He had a circumcised phallus and bilaterally descended smooth testes. No varicocele was present. Digital rectal examination revealed a very large prostate estimated to be over 100 mL in volume. The prostate was firm, smooth, and symmetric, with no tenderness noted. Laboratory evaluation revealed a WBC of 6.9, hematocrit of 38, and a serum creatinine of 1.3 mg/dL. Electrolytes and coagulation parameters were within the normal range. Mr. S subsequently had an intravenous pyelogram (IVP) with tomograms. The IVP suggested a left upper infundibular mass (Fig.1). The kidneys were otherwise radiographically normal, and no ureteral filling defects were noted. A prostatic impression was seen at the bladder neck. No other filling defects were present. Cystoscopy and bladder washings were subsequently performed. During cys- M SPRING 1999 REVIEWS IN UROLOGY 99 Bladder Tumors continued Figure 1. Initial IVP performed to evaluate episode of gross hematuria. Figure 2. Complex left renal mass on CT scan. toscopy, there was bloody efflux from the left ureteral orifice. The cystoscopy was otherwise unremarkable, and the cytology result from the bladder washings was normal. Mr. S was next scheduled for ureteroscopy, which revealed a normal ureter. However, blood was noted to efflux from the upper pole infundibulum. No tumor was seen during ureteroscopy. Mr. S was subsequently referred to our institution for a second opinion. At that time, a CT scan of the abdomen and pelvis with 5 mm cuts through the kidneys, with and with- Figure 3. Grade 3 clear-cell carcinoma in the left kidney. 100 REVIEWS IN UROLOGY SPRING 1999 out contrast, was obtained. The CT scan revealed 2 simple cysts in the right kidney measuring 4 to 5 cm each. The left kidney also contained several cysts ranging 2 to 4 cm in size. However, a 4 x 3 x 4 cm heterogenous enhancing mass in the anterior aspect of the left lower pole was also noted (Fig. 2). No venous extension or lymphadenopathy was appreciated. The prostate measured 112 mL in volume, with a prominent median lobe jutting into the bladder neck. After an informed consent, Mr. S was taken to the operating room, at which time he underwent a supra11th rib, left radical nephrectomy. He tolerated the procedure well. His serum creatinine stabilized at 1.9 mg/dL. Gross and histologic examination of the specimen revealed a grade 3/4 renal clear-cell carcinoma (RCC) extending into the renal pelvis, with no capsular penetration (Fig. 3). A concomitant grade 2/4 transitional cell carcinoma (TCC) of the renal pelvis was also noted (Fig. 4). The TCC was noninvasive. All margins, including the ureteral margin, were clear of tumor involvement. Bladder Tumors Given the concomitant presence of the TCC with the RCC and the fact that a left nephrectomy and not a left nephroureterectomy had been performed, potential therapeutic and surveillance options were discussed with Mr. S and his family. These options included reoperation with formal completion of the ureterectomy or surveillance with cystoscopy, left ureterograms, ureteral washings, and ureteroscopy of the ureteral stump. A decision was made not to reoperate but to follow the ureteral stump with endoscopic, radiographic, and cytologic evaluations. Follow-up surveillance consisted of CT scans and chest radiographs for evaluation of tumor recurrence and development of metastatic disease. Trimonthly cystoscopy and bladder washings with left retrograde ureterograms and cytologic evaluation were instituted for surveillance of the transitional epithelium. Because of the presence of a prominent median lobe, catheterization of the left ureteral orifice was challenging. Eight months after surgery, 3 small papillary tumors were noted along the anterior bladder wall and were resected (Fig. 5). They were all grade 1, noninvasive (Ta) TCC. When Mr. S redeveloped gross hematuria several weeks later, he was taken to the operating room, where Figure 4. Papillary TCC in the renal pelvis. Main points √ The demographics of patients with concomitant RCC and renal TCC are similar to the demographics of patients with RCC alone. √ Concomitant RCC and renal TCC occur most commonly in the left kidney. √ Renal TCC is usually managed with a nephroureterectomy, as renal TCC can be associated with a high risk of developing ureteral TCC. √ Although options for intravesical immunotherapy and chemotherapy are expanding for treatment of patients with bladder TCC, side effects and recurrence rates still strongly influence choices and timing. cystoscopy and evacuation of an estimated 2 units of blood were performed. Bleeding was noted from the median lobe of the prostate and controlled with fulguration and subsequent continuous bladder irrigation. After resolution of the gross hematuria, he was discharged home. Follow-up cystoscopies, retrograde ureterograms, and ureteral washings continued to be negative. Follow-up CT scans and chest x-rays were negative for tumor recurrence and development of metastatic disease. Ten months later, however, Mr. S re-presented with an episode of gross hematuria. Cystoscopy revealed 5 papillary tumors at the bladder neck. Ureteral washings were negative. Transurethral resection of the median lobe and the bladder tumors was performed. The tumors were grade 2, Ta TCC on the pathology report. No can- cer was noted in the resected prostate chips. Intravesical therapy with bacille Calmette-Guérin (BCG) was subsequently started. However, Mr. S could not tolerate the irritative voiding symptoms, and the BCG therapy was terminated. Mr. S has since redeveloped grade 2, Ta TCC of the bladder, and BCG intravesical therapy has been restarted. Thus far he has been able to tolerate the course of BCG therapy. Discussion Synchronous development of RCC and TCC in a kidney is a relatively unusual occurrence, with only 27 cases reported in the English literature to date.1-27 In fact, a review of over 700 cases of RCC spanning a 30year period at M.D. Anderson Hospital and Tumor Institute revealed only 1 case of synchronous RCC and Figure 5. Grade 1 Ta TCC in the bladder. SPRING 1999 REVIEWS IN UROLOGY 101 Bladder Tumors continued TCC in the same kidney (0.14%).17 Asynchronous development of RCC and TCC in kidneys treated with partial nephrectomy as well as RCC in a kidney and TCC of the ipsilateral ureter have also been described and remain uncommon occurrences.24,28 The demographics of patients with concomitant RCC and TCC are similar to the demographics of patients presenting with solitary RCC or TCC of the kidney.25 There is a higher predilection for men (2:1). The usual mode of presentation is with hematuria (90%), flank pain (19%), or a palpable mass (14%). The mean age of presentation is 65 years. These tumors, interestingly, occur with a 3fold higher frequency in the left kidney.25 Importantly, no association between development of synchronous RCC and TCC, and the presence of higher grade, more advanced stage of disease, or poorer prognosis has been noted.25 TCC accounts for 5% to 10% of all renal tumors.29,30 Recently, in an unpublished review of patients referred to UCLA for evaluation and treatment of presumed RCC, 7% actually had TCC of the kidney and had been misdiagnosed preoperatively as having RCC. A misdiagnosis can significantly impact the proposed therapy. The standard management of localized TCC of the kidney is a nephroureterectomy, because up to 84% recurrence rates in the ipsilateral ureter have been described.31-34 The treatment of a retained ureteral stump after a radical nephrectomy for an undiagnosed TCC is controversial. However, the increased incidence of ipsilateral ureteral recurrence associated with higher grades, higher stages, and the presence of multifocality of renal TCC certainly need to be considered. Whereas only a 7% recurrence rate in the ipsilateral ureteral stump is noted in patients with a solitary grade 1 tumor, this incidence increases to nearly 30% with grade 2 tumors.35,36 Higher 102 REVIEWS IN UROLOGY SPRING 1999 grades and the presence of multifocality are associated with even higher rates of ipsilateral ureteral recurrence.36 Furthermore, while low grade ureteral recurrences do not appear to compromise survival, higher grade recurrences are associated with poorer prognoses.32,35-37 In regards to Mr. S, the presence of a solitary noninvasive, grade 1 TCC of the renal pelvis is, therefore, associated with a relatively low rate of ipsilateral ureteral recurrence. Certainly close surveillance with endoscopic, radiographic, and cytologic evaluation remains important for his care. The development of synchronous or metachronous bladder tumors in patients with upper tract tumors has also been well substantiated. The incidence is approximately 45%.33,38-40 The development of bladder tumors in patients with upper tract TCC has been suggested to be due to downward seeding of tumor cells.41 In this case presentation, Mr. S developed grade 1, Ta TCC of his bladder shortly after diagnosis of his upper tract tumors. Despite having a 50% recurrence rate, TaG1 tumors portend a very low (2% to 5%) progression rate.42,43 For this reason, many would argue against the use of any intravesical immunotherapy or intravesical chemotherapy. Mr. S, however, developed multifocal recurrence of his Ta tumors and, with the recurrence, the grade of the tumors had progressed from grade 1 to grade 2. Given the grade progression and the short disease-free interval, intravesical BCG therapy was initiated. As reputed, BCG therapy is associated with a relatively high side-effect profile.44,45 The most frequently cited side effect is development of irritative voiding symptoms, which is noted in up to 90% of the patients receiving intravesical BCG therapy. These irritative symptoms are usually self-remitting, and patients can continue with the regular schedule of BCG therapy. In fact, many argue that the irritative voiding symptoms are a marker of effective intravesical BCG therapy and that the lack of symptoms may suggest an inadequate dose.46 BCG has clearly been shown to decrease recurrence and progression rates of bladder TCC and carcinoma in situ.45-50 Maintenance BCG therapy seems to provide even better longterm control.48-50 Unfortunately, the irritative voiding symptoms were initially intolerable to Mr. S, and the BCG therapy was held. Options available at this point included observation, restarting BCG therapy at a later date, or initiating other intravesical immunotherapeutic or chemotherapeutic agents. Review of the literature suggests a slight, if any, decrease in recurrence rates of bladder TCC when treated with transurethral resection (TUR) and intravesical chemotherapy (thiotepa, doxorubicin, ethoglucid, mitomycin-C, or cisplatin) as compared with TUR alone.51-56 No differences in progression rates or survival rates are noted, however. Of the intravesical chemotherapeutic agents evaluated to date, mitomycin-C is the most effective in decreasing bladder TCC recurrence rates. Intravesical interferon monotherapy has also not shown great promise for the treatment of TCC. Data on other intravesical immunotherapeutic agents such as keyhole limpet hemocyanin, bropirimine, and interleukin-2 are still sparse and incomplete. Initial results suggest that, although these agents may exhibit some efficacy in the treatment of TCC and in prevention of TCC recurrences, they are not as efficacious as intravesical BCG.57 This case presentation of the uncommon occurrence of synchronous RCC and TCC in a kidney raises several issues. The potential for misdiagnosing a renal TCC as an RCC and considerations regarding treatment of the retained ureteral stump after the nephrectomy have been highlighted. The high frequency of Bladder Tumors the development of bladder tumors in patients with upper tract TCC has also been illustrated. Lastly, potential modalities for the treatment of superficial and minimally invasive bladder TCC, as well as the purported efficacies and some of the associated side effects of these modalities, have been discussed. 19. 20. 21. References 1. Graves RC, Templeton ER: Combined tumors of the kidney. J Urol 5:517-37, 1921. 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Philadelphia, Williams and Wilkins, 1996, pp 416-427. 56. Lamm DL: Alternative immunotherapies for superficial bladder cancer, in, Vogelzang N, Scardino P, Shiply W, Coffey D. Comprehensive Textbook of Genitourinary Oncology. Philadelphia, Williams and Wilkins, 1996, pp 435-441. SPRING 1999 REVIEWS IN UROLOGY 103