Guidelines Summary
Guidelines for the diagnosis and management of upper urinary tract urothelial cell carcinoma have been issued by the following organizations:
Diagnosis
The NCCN states that patients with suspected upper tract urothelial carcinoma (UTUC), including both renal pelvis and ureteral tumors, should undergo cystoscopy, upper tract imaging with retrograde ureteropyelography, ureteroscopy with biopsy and/or selective washings, and optional urine cytology. A chest x-ray can help to evaluate for metastatic disease. Additionally, evaluation for Lynch syndrome should be considered, given the syndrome's high prevalence in patients with UTUC. [33]
Treatment
The NCCN provides treatment recommendations based on the location and disease extent, as follows [33] :
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Tumors that originate in the upper ureter typically are treated with nephroureterectomy with a cuff of bladder plus regional lymphadenectomy for high-grade tumors; a portion of the bladder is removed to ensure complete removal of the entire intramural ureter
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Endoscopic resection of upper ureter tumors is acceptable, but those are more commonly treated with nephroureterectomy with a bladder cuff, plus regional lymphadenectomy for high-grade tumors.
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Neoadjuvant chemotherapy should be considered in select patients, including patients with retroperitoneal lymphadenopathy, bulky (> 3cm) high-grade tumor, sessile histology, or suspected parenchymal invasion.
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Tumors that originate in the mid-portion are divided into small, low-grade tumors and large, high-grade tumors.
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Treatment of small, low-grade tumors is excision and ureteroureterostomy or complete ureterectomy and ileal ureter in highly selected patients; endoscopic resection; or, if the tumor cannot be managed endoscopically and the ureteral extent is too great, nephroureterectomy with a cuff of bladder may be considered.
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Nephroureterectomy with a cuff of bladder and regional lymphadenectomy is used for larger, high-grade lesions; neoadjuvant chemotherapy should be considered for selected patients.
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Distal ureteral tumors may be managed with a distal ureterectomy and reimplantation of the ureter (preferred if clinically feasible); endoscopic resection; or, in some cases, a nephroureterectomy with a cuff of bladder, with the addition of regional lymphadenectomy recommended for high-grade tumors.
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Nephroureterectomy is contraindicated in patients with bilateral disease, solitary kidney, kidney insufficiency, or a hereditary predisposition to genitourinary cancer; such patients should receive nephron-sparing treatment.
The EUA provides recommendations for conservative management, as well as recommendations for radical nephroureterectomy (RNU). The indications for RNU are as follows [32] :
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Suspicion of infiltrating UTUC on imaging
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High-grade tumor
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Multifocality (in patients with two functional kidneys)
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Noninvasive but large (> 2 cm) UTUC
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Neoadjuvant chemotherapy should be considered in all of these categories (however, this has not been adequately studied in randomized clinical trials)
Recommendations regarding RNU include the following:
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Open and laparoscopic access are equivalent in terms of efficacy
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Bladder cuff removal is imperative
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Several techniques for bladder cuff excision are acceptable, except stripping
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Lymphadenectomy is recommended
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Postoperative instillation chemotherapy in the bladder may prevent recurrence
The indications for conservative management are as follows:
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Unifocal tumor
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Tumor < 1 cm
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Low-grade tumor
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No evidence of an infiltrative lesion on CT urography
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Understanding of close follow-up
Recommendations regarding conservative treatment include the following:
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Flexible ureteroscopy is preferable to rigid ureteroscopy
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A percutaneous approach remains an option in small, low-grade calyceal tumors unsuitable for ureteroscopic treatment
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Ureteroureterostomy for noninvasive low-grade tumors of the proximal ureter or mid-ureter that cannot be removed completely by endoscopic means, and for high-grade or invasive tumors when renal-sparing surgery (RSS) for preservation of kidney function is a goal
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Complete distal ureterectomy and neocystostomy for noninvasive, low-grade tumors in the distal ureter that cannot be removed completely by endoscopic means and for high-grade, locally invasive tumors
Locally Advanced and Metastatic Disease Treatment
The NCCN guidelines recommend systemic therapy for locally advanced and metastatic disease. First-line preferred regimens (category 1) for cisplatin-eligible patients include [33] :
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Gemcitabine and cisplatin followed by avelumab maintenance therapy if no progression
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Dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (DDMVAC) with growth factor support followed by avelumab maintenance therapy if no progression
First-line preferred regimens for cisplatin ineligible patients include:
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Gemcitabine and carboplatin followed by avelumab maintenance therapy (category 1) if no progression
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Atezolizumab for patients whose tumors express programmed death ligand 1 (PD-L1) or who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 expression
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Pembrolizumab for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for any platinum-containing chemotherapy
Other recommended regimens include [33] :
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Gemcitabine
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Gemcitabine and paclitaxel
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Ifosfamide, doxorubicin, and gemcitabine for patients with good kidney function and good performance status (PS)
Second-line preferred regimens include [33] :
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Pembrolizumab (category 1 post-platinum)
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Immune checkpoint inhibitor (nivolumab or avelumab)
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Erdafitinib
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Enfortumab vedotin-ejfv
Other recommended second-line treatments include [33] :
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Paclitaxel
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Docetaxel
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Gemcitabine
The EAU guidelines generally concur with the NCCN recommendations but include a weak recommendation to offer RNU as palliative treatment for patients with locally advanced tumors. [32]
Follow-up and surveillance
The EAU recommends follow-up for at least 5 years after treatment of UTUC; however, the surveillance schedules specified are all grade C recommendations. Surveillance schedules are as follows [32] :
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Noninvasive tumors treated with RNU - Cystoscopy and urinary cytology at 3 months and then annually; CT annually
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Invasive tumors treated with RNU - Cystoscopy and urinary cytology at 3 months and then annually; CT urography every 6 months over 2 years and then annually. After 5 years of recurrence free years, recurrence risk is low and cystoscopy can be replaced with a less invasive surveillance regimen.
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If there are concerning lesions on cystoscopy, conducting endoscopy under anesthesia to obtain bladder biopsies is strongly recommended.
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Conservatively managed tumors - Urinary cytology and CT urography at 3, 6, and 12 months and annually thereafter; cystoscopy, ureteroscopy, and cytology in situ at 3 and 6 months, then every 6 months over 2 years, then annually
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There is a weak recommendation to conduct ultrasound if cystoscopy is not possible or refused by a patient.
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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.
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CT scan, delayed phase. Enhancing mass can be visualized in left renal pelvis (white arrows).
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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.
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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.
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Pathology specimen shows urothelial tumor of renal pelvis (white arrows).
