Renal Transitional Cell Carcinoma 

Updated: Nov 05, 2019
Author: Bagi RP Jana, MD, MBA, MHA, FACP; Chief Editor: E Jason Abel, MD 

Overview

Practice Essentials

Renal transitional cell carcinoma (TCC), or renal urothelial carcinoma (UC), is a malignant tumor arising from the transitional (urothelial) epithelial cells lining the urinary tract from the renal calyces to the ureteral orifice (see the image below). UC is the most common tumor of the renal pelvis. Over 80,000 cases of bladder cancer are diagnosed annually in the United States. Upper urinary tract TCC is estimated to occur in 5% of all urothelial cancers and in fewer than 10% of renal tumors. Evidence indicates that the frequency of upper urinary tract malignancies is increasing.[1]

Right retrograde pyelogram demonstrates large fill Right retrograde pyelogram demonstrates large filling defect in midureter due to transitional cell carcinoma (large arrow). Note characteristic appearance of radiographic contrast material just distal to obstruction (small arrow), which gives rise to so-called goblet sign. Contrast is also visible beyond partially obstructed segment of ureter in renal pelvis and collecting system.

See Renal Cell Carcinoma: Recognition and Follow-up, a Critical Images slideshow, to help evaluate renal masses and determine when and what type of follow-up is necessary.

Surgical intervention is the main form of radical treatment for localized disease. Medical therapy usually is administered as an adjuvant to surgical therapy or to patients in whom surgical treatment is contraindicated (eg, because of poor general condition or the presence of advanced disease). The role of radiation therapy in the management of upper urinary tract TCC is not well defined.

For patient education resources, see the Cancer Health Center, as well as Blood in the Urine (Hematuria).

Pathophysiology

TCC accounts for more than 90% of renal pelvic tumors; other cancer types seen include squamous cell carcinoma (SCC) and adenocarcinoma. The predominant histologic pattern of UC is a papillary tumor with stratified, nonkeratinizing epithelium supported on a thin fibrovascular core.

TCC of the upper urinary tract is histologically identical to urinary bladder cancer. These 2 malignancies share the same risk factors and can occur as a part of “field cancerization,” which results from exposure of urothelium to carcinogens excreted or activated in the urine. Hence, upper urinary tract urothelial tumors may be multifocal, and in 2-10% of cases, they are bilateral as well.

Patients with upper urinary tract urothelial tumors are at risk for the development of bladder tumors, which have an estimated incidence of 20-48%. Bladder cancer usually appears within 5 years. Patients with primary bladder cancer develop upper urinary tract UC in 2-4% of cases. The frequency of upper urinary tract UC may reach 21% in patients with bladder carcinoma in situ (CIS) and in those with certain occupational exposures.

Etiology

The exact cause of upper urinary tract TCC is not known; however, several risk factors have been identified.

Workers in the chemical, petrochemical, aniline dye, and plastics industries, as well as those exposed to coal, coke, tar, and asphalt, are at increased risk for renal pelvis and ureteral tumors.

Cigarette smoking appears to be the most significant acquired risk factor for upper urinary tract UC. It is suggested that 70% of upper urinary tract urothelial tumors in men and 40% of those in women can be attributed to smoking.

Two chronic tubulointerstitial disorders, Balkan endemic nephropathy and Chinese herbs nephropathy, are also risk factors for upper urinary tract urothelial tumors. Both have been linked to exposure to aristolochic acid.[2] Balkan endemic nephropathy is confined to regions located along the Danube River and its tributaries. It appears to result from dietary exposure to aristolochic acid in the seeds of Aristolochia clematitis (European birthwort), a native plant that may comingle with local wheat.[3] Chinese herbs nephropathy likely results from aristolochic acid found in certain herbal remedies used in traditional Chinese medicine.[2]

Analgesic abuse is a risk factor; a combination of phenacetin use and papillary necrosis results in a 20-fold increase in risk for renal urothelial tumors. Phenacetin was removed from the US market in 1983, and phenacetin-related upper urinary tract UC has become vanishingly rare.[4]

Chronic bacterial infection with urinary calculus and obstruction may predispose to the development of urothelial cancer. SCC is the most common entity in these cases. Schistosomiasis also may predispose to SCC.

The chemotherapy drugs cyclophosphamide and ifosfamide are implicated in the development of urothelial cancers in the upper and lower urinary tract, particularly after drug-induced hemorrhagic cystitis.

Epidemiology

United States statistics

According to American Cancer Society, an estimated 80,470 bladder cancers and 73,820 kidney cancers will be diagnosed in the United States in 2019. Primary malignancies of the ureters and other urinary organs, on the other hand, are much less common; it is estimated that 3930 such cancers will be diagnosed and 980 patients will die of this disease in 2019.[5] Deaths from urothelial malignancies have been decreasing since 1995.

International statistics

Worldwide statistics vary and are inaccurate, in that renal pelvis tumors are not reported separately. The highest incidence is found in Balkan countries (eg, Bosnia, Bulgaria, Croatia, Romania, and Serbia), where UCs account for 40% of all renal cancers and are bilateral in 10% of cases.

Age-, sex-, and race-related demographics

Renal pelvis tumors rarely occur before age 40 years. The peak incidence is in the 60- to 70-year age group. Men are affected approximately 2 times as frequently as women are. The incidence is slightly higher in African Americans than in other races; reported rates are similar among white Americans, Hispanics, and Native Americans. Renal pelvic tumors are less common in Asian Americans.

Prognosis

Renal UC is uniformly fatal unless it is treated. In a multicenter study of 1363 patients with upper urinary tract urothelial carcinoma who were treated with radical nephroureterectomy, the 5-year cancer-specific survival probability was approximately 73%.[6]

Tumor stage is the most important prognostic factor for upper urinary tract UC. Survival correlates closely with tumor stage. The TNM staging system developed by the International Union Against cancer (UICC) for upper urinary tract carcinomas is the most comprehensive (see Staging).

Tumor grade is another predictor of prognosis (see Histologic Findings). Tumor grade usually follows tumor stage, and patients with high-grade carcinomas have more advanced (ie, high-stage) disease. Stage and grade correlate in as many as 83% of cases, though stage remains a more accurate predictor of prognosis.

Patients with stage T3 renal tumors have a better prognosis than those with ureteral tumors. A retrospective study by Park et al found that in patients with stage pT3 disease, 5-year cancer-specific survival rates were 77.5% for renal pelvic tumors invading the renal parenchyma versus 49.7% for tumors invading peripelvic or periureteral fat; 5-year recurrence-free survival rates for the 2 tumor types were 75.6% and 32.0%, respectively.[7] The authors suggested that the thickness of the renal parenchyma may protect against local tumor spread.

The 5-year survival rate after radical surgery depends on the disease stage, as follows:

  • Stages Tis, Ta, or T1 – 91%
  • Stage T2 – 43%
  • Stages T3, T4, N1, or N2 – 23%
  • Stages N3 or M1 – 0%

TCC may develop in the contralateral kidney after radical nephroureterectomy. In a European multicenter dataset of patients who underwent nephroureterectomy for nonmetastatic TCC, a history of bladder TCC preceding the upper urinary tract TCC was the only predictor of TCC recurrence in the contralateral upper tract.[8] The 5-year probabilities of freedom from TCC in the contralateral upper tract TCC were as follows:

  • 96.6% for patients with de novo upper-tract disease
  • 91.1% for those having prior non–muscle-invasive bladder TCC
  • 55.3% for those with prior muscle-invasive bladder TCC

The 5-year survival rate in selected patients after conservative surgery is reported to be 70-90%.

Recurrences in the remaining urothelium after conservative treatment are relatively frequent because of the multifocal nature of TCCs. Ipsilateral recurrence rates may reach 25-50%. Most low-grade recurrences can be treated with repeat conservative excision. The 5-year survival rates in these patients with low-grade, low-stage disease can approach 100%.

The prognosis is poor for patients with advanced SCC.

Vecchi et al have developed and validated two nomograms for predicting overall survival in patients with metastatic UC. The nomograms are intended to be used before and after completion of first-line platinum-based chemotherapy for metastatic UC.[9]

Adverse prognostic factors in patients receiving salvage systemic therapy for advanced UC include the following[10] :

  • Eastern Cooperative Oncology Group (ECOG) performance status > 0
  • Liver metastasis
  • Hemoglobin level < 10 g/dL
  • < 3 months since prior chemotherapy
  • Albumin level below the lower limit of normal [11]
 

Presentation

History

Renal urothelial carcinoma (UC) is rarely reported as an incidental finding. Symptoms are significant enough to suggest the diagnosis in a relatively short time after disease development. A small percentage (1-2%) of patients are asymptomatic.

Gross hematuria is the most common presenting symptom, occurring in 75-95% of patients. Microscopic hematuria occurs in 3-11% of patients.

Approximately 14-37% of patients report pain. Pain is usually dull and is caused by the gradual obstruction of the collecting system. Renal colic also may occur with the passage of blood clots.

Physical Examination

The physical examination usually is not informative or specific, especially in patients with early-stage disease. A palpable flank mass may be noted in fewer than 20% of patients. The classic clinical triad of hematuria, pain, and mass is also rare (15%) and is usually an indicator of advanced disease.

 

 

DDx

 

Workup

Laboratory Studies

Urinalysis and urine culture are indicated. The presence of microscopic hematuria suggests urinary tract tumors, which must be ruled out even if the hematuria resolves. The presence of more than 2-5 red blood cells (RBCs) per high-power field (HPF) is considered sufficient to warrant further investigation to rule out upper urinary tract renal transitional cell carcinoma (TCC). Evaluate for urinary tract infections.

Cytologic studies may be helpful. Voided-urine cytology is a convenient and noninvasive method of diagnosis, but it is subjective and lacks the necessary sensitivity for diagnosing upper urinary tract urothelial tumors, especially low-grade neoplasms. Fluoroscopically guided brush biopsy increases the diagnostic accuracy to 80-90%.

A 2012 study concluded that urine cytology and fluorescence in situ hybridization (FISH) are the single tests with best overall performance for the detection of urothelial carcinoma. Combining cytology and FISH improved the sensitivity; failure of cytology to detect grade 3 carcinoma in situ tumors decreased by 62.5% when FISH was performed in cytology-negative patients.[12]

Intravenous Urography

In the past, intravenous urography (IVU) was the most commonly used diagnostic method for the evaluation of patients with hematuria in the past. In current practice, however, it is increasingly being replaced by computed tomography (CT) urography.[13]

Filling defects in the upper urinary tract can be demonstrated in 50-75% of patients. Other common causes of filling defects (eg, nonopaque stones, blood clots, papillary necrosis with sloughing, and fungus balls) should be ruled out. In 13-31% of cases, the affected kidney may not be adequately visualizable.

Computed Tomography

CT scanning is useful in the diagnosis and staging of renal urothelial tumors (see the images below). It can distinguish between radiolucent renal stones and upper urinary tract urothelial tumors, in that stones appear opaque on CT scans (>200 Hounsfield units [HU] for uric acid stones versus 60-80 HU for tumors).[14]

CT scan with contrast, vascular phase. Mass can be CT scan with contrast, vascular phase. Mass can be seen in left renal pelvis (black arrows). Patient underwent nephroureterectomy. Tumor was high-grade urothelial carcinoma invading subepithelial tissue (stage T1) and measuring 7.5 × 3.2 × 3 cm.
CT scan, delayed phase. Enhancing mass can be visu CT scan, delayed phase. Enhancing mass can be visualized in left renal pelvis (white arrows).

CT scanning also can be used for determining the local extent the tumor and the presence of distant metastases, but it is of limited value in predicting the pathologic stage of upper urinary tract urothelial tumors (it is accurate in 43-77% of cases).

Cystoscopy and Ureteroscopy

Cystoscopy may help to localize bleeding site (left or right) and rule out or confirm concomitant bladder lesions. Retrograde pyelography (RPG) is especially useful when the kidney cannot be visualized by means of IVU or when renal insufficiency or severe contrast allergy prevents the performance of IVU. A properly performed RPG is confirmatory in approximately 85% of cases (see the images below).

Retrograde pyelography. Filling defect can be seen Retrograde pyelography. Filling defect can be seen in left renal pelvis and lower calyx (black arrows). Patient underwent left nephroureterectomy. Tumor was low-grade urothelial carcinoma measuring 2.5 × 2 × 1 cm.
Right retrograde pyelogram demonstrates large fill Right retrograde pyelogram demonstrates large filling defect in midureter due to transitional cell carcinoma (large arrow). Note characteristic appearance of radiographic contrast material just distal to obstruction (small arrow), which gives rise to so-called goblet sign. Contrast is also visible beyond partially obstructed segment of ureter in renal pelvis and collecting system.

Ureteroscopy is routinely used in the diagnosis of renal pelvic tumors. The correct diagnosis can be achieved in 80-90% of cases. The gross appearance usually suffices for the diagnosis of upper urinary tract urothelial carcinoma (UC); however, a biopsy should be obtained if necessary.

Histologic Findings

Most TCCs are papillary. They may be single or multiple. See image below.

Pathology specimen shows urothelial tumor of renal Pathology specimen shows urothelial tumor of renal pelvis (white arrows).

Flat carcinoma in situ (CIS) also may develop in the renal pelvis. CIS may be found in the distal ureter of 20-35% of patients who undergo cystectomy for bladder cancer. The presence of CIS warrants further resection of the ureter until a healthy ureteral segment is reached.

UCs can be characterized according to the degree of nuclear anaplasia. Low-grade tumors may have a thin fibrovascular core that is covered by several layers of cytologically benign urothelium, or they may be more broad-based, with hyperplastic urothelium. High-grade tumors usually are solid masses of large cells with irregular nuclei. Tumor grade is an important predictor of prognosis.

Staging

The TNM staging system of the International Union Against Cancer (UICC) is used to stage upper urinary tract carcinomas.

Primary tumor (T) classifications include the following:

  • TX – Primary tumor is occult and cannot be assessed

  • T0 – No evidence of primary tumor

  • Ta – Papillary noninvasive carcinoma

  • Tis – Carcinoma in situ

  • T1 – Carcinoma involves subepithelial connective tissue

  • T2 – Carcinoma invades the muscularis

  • T3 – Carcinoma invades beyond muscularis into periureteric or peripelvic fat or into renal parenchyma

  • T4 – Carcinoma invades adjacent organs or extends through the kidney into perinephric fat

Regional lymph node (N) classifications include the following:

  • NX – Regional lymph nodes cannot be assessed

  • N0 – No regional lymph node metastasis

  • N1 – Metastasis in a single lymph node, 2 cm or less in greatest dimension

  • N2 – Metastasis in a single lymph node 2-5 cm in greatest dimension; or multiple metastatic lymph nodes, none more than 5 cm in greatest dimension

  • N3 – Metastasis in a lymph node more than 5 cm in greatest dimension

Distant metastasis (M) classifications include the following:

  • MX – Presence of distant metastasis cannot be assessed

  • M0 – No distant metastasis

  • M1 – Distant metastasis

 

Treatment

Approach Considerations

Once the diagnosis of upper urinary tract transitional cell carcinoma (TCC) has been made, treatment is mandatory. Surgical intervention is the main form of radical treatment for localized disease.

Local immunotherapy or chemotherapy can be attempted as an independent treatment method in cases of carcinoma in situ (CIS) or to reduce the recurrence rate after endoscopic management of upper urinary tract urothelial carcinoma (UC).

The role of radiation therapy in the management of upper urinary tract transitional cell carcinoma (TCC) is not well defined. Some studies suggest that radiation therapy may have some effect as adjuvant therapy to improve local control after radical surgical treatment for high-grade disease.

Medical therapy is usually indicated for patients with advanced disease or in whom surgical treatment is contraindicated (eg, because of poor general condition or the presence of advanced disease). Given the lack of data from randomized trials, routine use of neoadjuvant or adjuvant chemotherapy is not recommended.

 

 

 

Topical Immunotherapy or Chemotherapy

As a rule, local treatment is administered as adjuvant therapy, after endoscopic treatment of the UC, to decrease the recurrence rate. Methods of delivery vary (eg, irrigation through a ureteroscopic catheter or intravesical instillation after vesicoureteral reflux is ensured); however, irrigation through a percutaneous nephrostomy catheter is the most reliable method.

Bacille Calmette-Guérin

Instillation of bacille Calmette-Guérin (BCG) through a percutaneous catheter resulted in conversion of urine cytology from positive to negative in 7 of 10 patients with upper urinary tract CIS. BCG sepsis was observed in 1 patient and was treated successfully.

Administration of BCG as a prophylactic agent after endoscopic treatment of superficial urothelial tumors resulted in a recurrence rate of 12.5% in 1 study. However, some studies reported a recurrence rate of up to 50%.

In contrast to the efficacy of BCG in bladder cancer, the ability of BCG to treat high-grade UC of the upper urinary tract or reduce the progression rate is not determined. Therefore, high-grade upper urinary tract UC requires radical surgical intervention.

A retrospective study by Rastinehad et al compared 50 cases in which adjuvant BCG was given after resection of upper urinary tract TCC with 39 control cases. In treated cases, BCG was started 2 weeks after endoscopic management and given for a total of 6 courses. The comparison showed no overall benefit from BCG with regard to disease recurrence, interval to recurrence, and progression of disease.[15]

Mitomycin-C

Rates of progression and recurrence of upper urinary tract UC after treatment with mitomycin-C are comparable to those after treatment with BCG. However, the possibility of complications is much less with mitomycin-C, making it more attractive as a first-line agent in the secondary prophylaxis of upper urinary tract UC. In 1 study, irrigation with mitomycin-C reduced the recurrence rate to 14.2%.

Complications

Seeding through the nephrostomy tract remains a concern during percutaneous management; at least 1 case has been reported. Other serious complications of percutaneous treatment include perforation (5.5%) and ureteropelvic-junction stricture (1.4%). The frequency of stricture is much lower after percutaneous treatment than after ureteroscopy.

Systemic Chemotherapy

The combination of methotrexate, vinblastine, doxorubicin (Adriamycin), and cisplatin (MVAC) is the best-studied chemotherapy regimen for upper urinary tract TCC. Durable, complete responses were obtained in only 5-10% of patients. Serious complications were encountered in 41% of patients; treatment-related mortality was 2-4%.

Gemcitabine-based combinations (gemcitabine + cisplatin or carboplatin) have activity similar to MVAC in bladder cancer but are associated with less toxicity.[16] Some studies found the combination of gemcitabine and paclitaxel to be as effective as cisplatin-based therapies, with less nephrotoxicity. However, in a study compared the incidence of vascular thromboembolic events (VTEs) in patients with metastatic or unresectable UC who were treated with gemcitabine and carboplatin (GCb); gemcitabine, carboplatin, and bevacizumab (GCbBev), or gemcitabine and cisplatin (GCis), researchers found high incidence (>20%) of VTEs in patients treated with GCb and GCbBev.[17]

A meta-analysis by Giannatempo et al concluded that adding a taxane (paclitaxel or docetaxel) to gemcitabine and platinum as first-line therapy for advanced or metastatic UC showed a trend for improved overall survival. Median overall survival with taxanes was 15.5 mo, versus 12.5 mo without taxanes (P=0.056). However, the addition of a taxane led to an increase in grade 3 or higher neurotoxicity P=0.051), regardless of the specific platinum agent used.[18]

In a retrospective study, DiLorenzo and colleagues found that approximately half of the patients treated with second-line chemotherapy went on to receive third-line treatment. The study also found the median overall survival associated with the use of third-line chemotherapy was 31 (28–36) weeks. Significantly longer overall survival was seen in patients receiving single-agent cyclophosphamide than in patients treated with platinum-based combinations.[19]

Immunotherapy with checkpoint inhibitors is a promising development in the treatment of urothelial carcinoma. Atezolizumab, a monoclonal antibody to programmed death ligand 1 (PD-L1), was approved in May 2016 for treatment of locally advanced or metastatic urothelial carcinoma of the bladder in patients who have disease progression during or following platinum-containing chemotherapy, or disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.[20]

A phase II trial of atezolizumab as first-line treatment in previously untreated patients with locally advanced or metastatic urothelial cancer who were ineligible for cisplatin therapy demonstrated encouraging durable response rates, survival, and tolerability.[21]

Nivolumab, a monoclonal antibody to programmed death–1 receptor (PD-1) was approved in February 2017 for treatment of locally advanced or metastatic urothelial carcinoma of the bladder in patients who have disease progression during or following platinum-containing chemotherapy, or disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.[22]

Clinical trials of other immune checkpoint inhibitors, including pembrolizumab, durvalumab, avelumab, and a combination of nivolumab and ipilimumab are in advanced stages, and are expected to lead to approval of many of these agents or combinations in the near future.[23]

Alterations in the gene encoding fibroblast growth factor receptor (FGFR) are common in urothelial carcinoma and may be associated with lower sensitivity to immunotherapy. In an open-label phase II study of erdafitinib, a tyrosine kinase inhibitor of FGFR1-4, Loriot et al reported an objective tumor response in 40% of previously treated patients with locally advanced and unresectable or metastatic urothelial carcinoma with FGFR alterations.[24]

Surgical Resection

Patients with low-stage, low-grade tumors respond well to either radical or conservative surgical treatment. In a retrospective review of patients treated with renal-sparing ureteroscopic management, Pak et al reported that renal preservation approached 81%, with cancer-specific survival of 94.7% and significant cost savings over the cost of nephroureterectomy; these authors recommend conservative endoscopic management as the gold standard for low-grade and superficial-stage disease.[25] However, preoperative cytology and ureterorenoscopically-performed biopsies have limited accuracy in predicting the correct tumor grade. Additional diagnostic procedures should be done prior to definitive surgical intervention.[26]

Patients with high-stage, high-grade tumors respond poorly to either radical surgery or conservative surgery.

Patients with positive cytologic findings but normal radiographic and endoscopic examinations are not treated but are monitored closely by means of periodic intravenous urography (IVU) or retrograde pyelography (RPG).

Radical nephroureterectomy

Traditional radical surgery for renal UC consists of total nephroureterectomy with excision of a bladder cuff around the ureteral orifice. Otherwise, 30-75% of patients develop tumor recurrence in the ureteral stump or around the ipsilateral ureteral orifice. Transection of the ureter must be avoided because of the high risk of tumor spillage in the retroperitoneum.

Oncologically, laparoscopic or hand-assisted laparoscopic nephroureterectomy is as effective for localized disease as an open technique would be.[27, 28] In general, the laparoscopic approach is accompanied by less blood loss, less pain and discomfort, faster recovery, and shorter hospital stay. Trocar site recurrence is very rare; to date, 3 cases have been reported.[29]

Patients with poorly differentiated tumors or high-stage disease (especially those with microscopic lymph node involvement) may benefit from extensive retroperitoneal lymphadenectomy. However, the benefit is marginal, and appropriate candidates must be chosen carefully.

Conservative open surgical treatment

Conservative excision for upper urinary tract urothelial tumors includes segmental ureteral resection with reanastomosis or ureteroneocystostomy and partial nephrectomy. Conservative management is especially appropriate for solitary or functionally dominant kidneys, bilateral tumors, or small, low-grade ureteral tumors.

Upper ureteral and midureteral tumors may be treated with segmental resections if they are low-grade, solitary lesions.

Distal ureteral tumors may be treated with distal ureterectomy and ureteral reimplantation if no evidence of multifocality is noted. In these cases, distal ureterectomy may be as successful as total nephroureterectomy because proximal spread of UC after resection is rare.

Partial nephrectomy may be performed in patients with localized renal pelvic tumors; however, this approach should be employed only in situations requiring avoidance of renal failure.

Endoscopic Treatment

Urothelial tumors of the upper urinary tract can be excised by means of endoscopy in much the same fashion as superficial bladder tumors are. Indications for endoscopic management are the same as those for conservative resection and include low-grade tumors, bilateral involvement, and compromised renal function that necessitates a nephron-sparing approach.

Electrocautery and fulguration are used most commonly in the endoscopic setting. Currently, lasers (Ho:YAG and Nd:YAG) are being used for management of low-grade upper urinary tract urothelial tumors.

In cases of larger low-grade tumors with low metastatic potential, which cannot be eliminated during one session, ureteroscopic management can be performed several times.

Tumor size (>1.5 cm), multifocal disease, and high-grade tumors are the main risk factors for recurrence after ureteroscopic management of upper urinary tract UC. The presence of high-grade or invasive tumors, which cannot be eradicated endoscopically, necessitates radical surgical intervention (usually involving open or laparoscopic nephroureterectomy).

Complications

Perforation (0-10%) and stricture formation (5-13%) are the major complications of ureteroscopic treatment. Use of lasers (especially the Ho:YAG laser, which has low tissue penetration) may decrease the rate of stricture formation.

Long-Term Monitoring

Because of the high risk of local and bladder recurrences, long-term follow-up care for these patients is mandatory. Include ureteroscopy, cystoscopy, and either IVU or RPG in the routine follow-up procedures.

Urine markers are used more and more frequently in the follow-up of patients with UCs. The specificity of these tests (eg, BTA Stat [Polymedco, Cortlandt Manor, NY], ImmunoCyt [Scimedx, Denville, NJ], and fluorescence in situ hybridization [FISH]) is acceptable for follow-up, and their sensitivity is much better than that of urine cytology.

 

Medication

Medication Summary

The goals of pharmacotherapy are to induce remission, reduce morbidity, and prevent complications. The combination of methotrexate, vinblastine, doxorubicin (Adriamycin), and cisplatin (MVAC) is the best-studied chemotherapy regimen for upper urinary tract transitional cell carcinoma (TCC). Durable, complete responses were obtained in only 5-10% of patients. Serious complications were encountered in 41% of patients; treatment-related mortality was 2-4%.

Gemcitabine-based combinations (gemcitabine + cisplatin or carboplatin) have activity similar to MVAC in bladder cancer but are associated with less toxicity. Some studies found the combination of gemcitabine and paclitaxel to be as effective as cisplatin-based therapies, with less nephrotoxicity.

Immune checkpoint inhibitor therapy (ie, atezolizumab, nivolumab) is the newest option for treatment of locally advanced or metastatic disease.

Antineoplastics, Other

Class Summary

Antineoplastic agents inhibit cell growth and proliferation.

Methotrexate

Methotrexate inhibits dihydrofolate reductase (DHFR), causing a block in the reduction of dihydrofolate to tetrahydrofolate. This inhibits the formation of thymidylate and purines and arrests DNA, RNA, and protein synthesis.

Vinblastine

A vinca alkaloid with cytotoxic effect via mitotic arrest, vinblastine binds to a specific site on tubulin, prevents polymerization of tubulin dimers, and inhibits microtubule formation. Intrathecal (IT) administration may result in death.

Doxorubicin (Adriamycin)

Doxorubicin is an anthracycline antibiotic that causes DNA strand breakage through effects on topoisomerase II and direct intercalation into DNA, which causes DNA polymerase inhibition. This drug is both mutagenic and carcinogenic.

Cisplatin

Cisplatin is a platinum-containing compound that exerts an antineoplastic effect by covalently binding to DNA, with preferential binding to N-7 position of guanine and adenosine. It can react with 2 different sites on DNA to produce cross-links. The platinum complex also can bind to nucleus and cytoplasmic protein.

Gemcitabine (Gemzar)

Gemcitabine is a cytidine analog. After intracellular metabolism to its active nucleotide, it inhibits ribonucleotide reductase and competes with deoxycytidine triphosphate for incorporation into DNA.

Carboplatin

Carboplatin is an analog of cisplatin. This is a heavy metal coordination complex that exerts its cytotoxic effect by platination of DNA, a mechanism analogous to alkylation, leading to interstrand and intrastrand DNA cross-links and inhibition of DNA replication. It binds to protein and other compounds containing an SH group. Cytotoxicity can occur at any stage of the cell cycle, but the cell is most vulnerable to the action of these drugs in the G1 and S phase. Carboplatin has the same efficacy as cisplatin but with a better toxicity profile. The main advantages over cisplatin include less nephrotoxicity and ototoxicity (not requiring extensive prehydration) and a lower likelihood of inducing nausea and vomiting; however, it is more likely to induce myelotoxicity.

PD-1/PD-L1 Inhibitors

Class Summary

Programmed death ligand 1 (PDL1)  is expressed on the surface of activated T cells under normal conditions. Binding PDL1 inhibits immune activation and reduces T-cell cytotoxic activity when bound.

Atezolizumab

Indicated for locally advanced or metastatic urothelial carcinoma in patients who have disease progression during or following platinum-containing chemotherapy, or disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

Nivolumab (Opdivo)

Indicated for treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with a platinum-containing chemotherapy.

FGFR Inhibitors

Class Summary

Fibroblast growth factor receptor (FGFR) inhibitor; FGFRs are a family of receptor tyrosine kinases. Inhibition of FGFR phosphorylation and signaling decreases cell viability in cell lines expressing FGFR genetic alterations, including point mutations, amplifications, and fusions.

Erdafitinib

Indicated for locally advanced or metastatic urothelial carcinoma that has fibroblast growth factor receptor-2 (FGFR2) or FGFR3 genetic alterations and progressed during or following at least 1 line of prior platinum-containing chemotherapy, including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy.

 

Questions & Answers

Overview

What is renal transitional cell carcinoma?

What is the pathophysiology of renal transitional cell carcinoma?

What causes renal transitional cell carcinoma?

What is the prevalence of renal transitional cell carcinoma in the US?

What is the global prevalence of renal transitional cell carcinoma?

Which patient groups have the highest prevalence of renal transitional cell carcinoma?

What is the prognosis of renal transitional cell carcinoma?

What are the survival rates for renal transitional cell carcinoma?

What are the prognostic factors of renal transitional cell carcinoma?

Presentation

Which clinical history findings are characteristic of renal transitional cell carcinoma?

What are physical exam findings in patients with renal transitional cell carcinoma?

DDX

What are the differential diagnoses for Renal Transitional Cell Carcinoma?

Workup

What is the role of lab tests in the workup of renal transitional cell carcinoma?

What is the role of IV radiography in the workup of renal transitional cell carcinoma?

What is the role of CT in the workup of renal transitional cell carcinoma?

What is the role of cystoscopy and ureteroscopy in the workup of renal transitional cell carcinoma?

Which histologic findings are characteristic of renal transitional cell carcinoma?

How is renal transitional cell carcinoma staged?

Treatment

How is renal transitional cell carcinoma treated?

What is the role of topical therapies in renal transitional cell carcinoma treatment?

What is the role of bacille Calmette-Guérin (BCG) in renal transitional cell carcinoma treatment?

What is the role of mitomycin-C in renal transitional cell carcinoma treatment?

What are the possible complications of percutaneous treatment of renal transitional cell carcinoma?

What is the role of systemic chemotherapy in renal transitional cell carcinoma treatment?

What is the role of surgery in renal transitional cell carcinoma treatment?

What is the role of radical nephroureterectomy in renal transitional cell carcinoma treatment?

What is the role of conservative open surgery in renal transitional cell carcinoma treatment?

What is the role of endoscopy in renal transitional cell carcinoma treatment?

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What is included in long-term monitoring of renal transitional cell carcinoma?

Medications

What is the role of medications in renal transitional cell carcinoma treatment?

Which medications in the drug class PD-1/PD-L1 Inhibitors are used in the treatment of Renal Transitional Cell Carcinoma?

Which medications in the drug class Antineoplastics, Other are used in the treatment of Renal Transitional Cell Carcinoma?

Which medications in the drug class FGFR Inhibitors are used in the treatment of Renal Transitional Cell Carcinoma?