Endoscopic Diagnosis and Management of Upper Tract Urothelial Carcinoma

NYU Case of the Month, June 2019

Case of the Month Endoscopic Diagnosis and Management of Upper Tract Urothelial Carcinoma NYU Case of the Month, June 2019 James F. Borin, MD Department of Urology, NYU School of Medicine, New York, NY [Rev Urol. 2019;21(2/3):123–126] © 2019 MedReviews®, LLC A 67-year-old woman presented with a single episode of painless gross hematuria. She had a history of microscopic hematuria, and, 3 years ago, she had a negative workup, including a CT urogram and a cystoscopy. She also has a congenital solitary right kidney. She has never smoked and has no history of radiation, exposures to toxins, or excessive nonsteroidal anti-inflammatory drug (NSAID) use. Her workup consisted of urine cytology, which was negative; a cystoscopy, which was only remarkable for an absent left ureteral orifice; and a CT urogram, which showed filling defects in the right upper to mid pole calyces. She was then referred to NYU Langone Health for further evaluation, where an MRI urogram demonstrated a 1.9 cm 3 1.4 cm enhancing soft tissue lesion in the right upper pole calyx consistent with a urothelial neoplasm (Figure 1). Pre-operative Data BUN: 20 Creatinine: 0.98 mg/dL eGFR: 60 Urine cytology: negative for high-grade malignancy Urinalysis: 0 RBC Management In the operating room, cystoscopy showed normal bladder mucosa with a normal right ureteral orifice and an absent left ureteral orifice. A semi-rigid ureteroscope was used to evaluate the distal ureter and then a flexible ureteroscope was used for the proximal ureter; no ureteral tumors were seen. In the kidney, there was a papillary lesion in the upper pole consistent with urothelial carcinoma. At this point, an 11.5F 3 35 cm ureteral access sheath was passed into the proximal ureter and a 1.9 F nitinol basket with 12-mm diameter was used to resect the lesion in pieces. About 10 passes of the basket were made to remove most of the tumor. The base of the tumor was then fulgurated with a 365-μm holmium laser at settings of 0.8 J and 8 Hz and then 0.3 J and 40 Hz. Five of the largest tumor specimens were placed together in normal saline and sent for histopathology. Then a cytopathology specimen was prepared as follows: the remaining 5 pieces of tumor were placed in 10 cc of Hanks’ Balanced Salt Solution and mechanically morcellated with forceps; 10 cc of fluid was aspirated from the renal pelvis via the ureteroscope and added to the mixture and the entire specimen was sent for cytopathology. Histopathology and cytopathology both revealed urothelial carcinoma, low grade. Vol. 21 No. 2/3 • 2019 • Reviews in Urology • 123 Endoscopic Diagnosis and Management of UTUC continued The patient underwent 4 cycles of neoadjuvant chemotherapy with gemcitabine and cisplatin followed by robot-assisted nephroureterectomy. Surgery was challenging because there were adhesions between the upper pole of the kidney and the liver from the prior adrenalectomy. Pathology revealed renal calculi, chronic pyelonephritis, a 1-cm area of inflammatory changes and atypia in the upper pole, and no evidence of residual disease. Comment Figure 1. MRI urogram demonstrating a 1.9-cm enhancing soft tissue lesion (arrow) in the upper pole calyx of a solitary right kidney. Due to the large tumor volume, complete eradication was not ensured during the first procedure; therefore, the patient was taken back to the operating room a month later for a second look. There was a 1-cm area of papillary changes in the upper pole and this was ablated with the laser. At the conclusion of the procedure, a single-J ureteral catheter was placed in the upper pole and 40 mg of mitomycin in 20 mL sterile water was instilled at a rate of 1 mL/min. Case 2 A 68-year-old woman with a long history of kidney stones presented with an episode of painless gross hematuria that did not seem to be associated with stone passage. Four years before she presented at NYU Langone, she had several shockwave lithotripsy procedures—4 on the right kidney and 3 on the left kidney. She had been followed for the last few years with renal ultrasounds for asymptomatic bilateral small renal stones. She had a remote history of smoking, having quit more than 30 years ago, and she had an adrenalectomy for adrenocortical carcinoma 15 years ago. Urine cytology showed cytological atypia, and a CT urogram demonstrated a 2.0 cm 3 1.2 cm right upper pole enhancing soft tissue lesion suspicious for urothelial carcinoma (Figure 2). Pre-operative Laboratory Results Creatinine: 0.7 mg/dL Management The patient was taken to the operating room; cystoscopy demonstrated a normal bladder without lesions. Flexible ureteroscopy demonstrated several upper pole papillary lesions, in aggregate measuring about 2 cm. A ureteral access sheath was then placed to facilitate biopsy. A basket was used to remove multiple pieces of tumor and the specimens were divided; half were sent for pathology and the rest were morcellated and combined with washings from the renal pelvis and sent for cytology. Both histopathology and cytology revealed highgrade urothelial carcinoma. 124 • Vol. 21 No. 2/3 • 2019 • Reviews in Urology These two cases reflect the variability of upper tract urothelial carcinoma (UTUC) and the importance of factors beyond tumor size. The first patient had a prior negative workup for microscopic hematuria but developed gross hematuria, which prompted a repeat evaluation. Her tumor size was on the borderline for endoscopic management, but because she had a solitary kidney, a nephron-sparing approach was chosen. Although she has had a few local recurrences since her surgery, they have been easily managed endoscopically and she is tumor-free at present. The second patient had a remote history of smoking as well as recurrent nephrolithiasis, both of which have been associated with the development of UTUC.1,2 Although her tumor burden was like that of the first patient, it was high-grade (unfavorable risk), so she required treatment with neoadjuvant chemotherapy and nephroureterectomy. She subsequently developed stage III/IV chronic kidney disease, so she cannot be followed with CT urograms. Because of her history of kidney stones, she requires regular ultrasounds to assess for any new stone growth as well as MRI urograms to rule out any contralateral tumor recurrence. Endoscopic Diagnosis and Management of UTUC Figure 2. CT urogram demonstrating multiple stones in the right kidney, as well as a 2-cm enhancing soft tissue mass (arrow) in the upper pole calyx consistent with urothelial neoplasm. Surgical clips can be seen in the right upper quadrant from the prior adrenalectomy. Guidelines from both the National Comprehensive Cancer Network (NCCN) and the European Association of Urology (EAU) provide risk stratification criteria for patients with UTUC.3,4 NCCN defines favorable risk as low-grade, unifocal papillary tumors ,1.5 cm without evidence of invasion on cross-sectional imaging. EAU includes tumors ,2.0 cm in the low-risk group. Both guidelines advocate a nephron-sparing approach for these patients as results are equivalent between ureteroscopic, percutaneous, and extirpative (nephroureterectomy) management. Imperative indications for nephron sparing include bilateral lesions, a solitary kidney, chronic kidney disease, and hereditary predisposition (hereditary nonpolyposis colorectal cancer/Lynch syndrome). Although a nephron-sparing approach has been shown to have long-term survival like nephroureterectomy in low-/favorable-risk patients, these patients are prone to local recurrences. Unfortunately, currently available topical treatment options have minimal efficacy and are complicated to administer. A new treatment on the horizon, UGN-101, a reverse thermal hydrogel containing mitomycin, may offer hope to those with recurrent low-risk disease. In a multi-institutional phase III trial of 68 patients with low-grade upper tract urothelial carcinoma—48% of whose tumors were considered unresectable—60% achieved a complete response rate after 6 weekly instillations of UGN-101 and there was only a 7% relapse rate within the first 9 months.5 Adverse events included urinary tract infection and ureteral stricture. This is an investigational new drug that has not yet received FDA approval. Unfavorable (NCCN) or high-risk (EAU) factors include multifocal or sessile lesions, papillary tumors .1.5 to 2.0 cm, high-grade cytology or biopsy, hydronephrosis, evidence of invasion on cross-sectional imaging, or a tumor crossing the ureteropelvic junction. It may be reasonable to omit ureteroscopy in some of these patients prior to extirpative surgery as it has been associated with an increased risk of bladder cancer recurrence, though not of decreased overall survival.6 For most patients, endoscopic evaluation is imperative to identify candidates for nephron sparing—for lower-volume, low-risk tumors— or for neoadjuvant chemotherapy for high-risk tumors. There are several instruments that can be used for biopsy. In comparison to a standard 3F biopsy forceps, use of a 6F backloading biopsy forceps with a 4 mm3 cup size or a nitinol stone basket increases the yield of samples deemed adequate for histological characterization and shows higher concordance with final grade on nephroureterectomy specimens.7,8 However, because histopathology specimen Vol. 21 No. 2/3 • 2019 • Reviews in Urology • 125 Endoscopic Diagnosis and Management of UTUC continued processing can result in equivocal results, particularly with small samples, a specimen should also be sent for cytopathology.7 A few biopsy samples can be set aside and then gently morcellated with forceps to be added to a sample of urine taken from the area surrounding the tumor after biopsy has been performed. This may reduce the chances of missing a high-grade tumor. References 1. 2. 3. 4. van de Pol JAA, van den Brandt PA, Schouten LJ. Kidney stones and the risk of renal cell carcinoma and upper tract urothelial carcinoma: the Netherlands Cohort Study. Br J Cancer. 2019;120:368-374. Cheungpasitporn W, Thongprayoon C, O’Corragain OA, et al. The risk of kidney cancer in patients with kidney stones: a systematic review and meta-analysis. QJM. 2015;108:205-212. National Comprehensive Cancer Network. Bladder Cancer (version 3.2019). http://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf. Accessed May 11, 2019. European Association of Urology Guidelines. Upper urinary tract urothelial cell carcinoma. https:// uroweb.org/guideline/upper-urinary-tract-urothelialcell-carcinoma. Accessed May 11, 2019. 126 • Vol. 21 No. 2/3 • 2019 • Reviews in Urology 5. 6. 7. 8. Kleinmann N, Gan R, Matin S, et al. Nephron-sparing management of low grade (LG) UTUC with UGN-101 (mitomycin gel) for instillation: the Olympus Trial experience. J Urol. 2019;201(suppl 4):e999. Guo RQ, Hong P, Xiong GY, et al. Impact of ureteroscopy before radical nephroureterectomy for upper tract urothelial carcinomas on oncological outcomes: a meta-analysis. BJU Int. 2018;121:184-193. Breda A, Territo A, Sanguedolce F, et al. Comparison of biopsy devices in upper tract urothelial carcinoma. World J Urol. 2019;37:1899-1905. Lama DJ, Safiullah S, Patel RM, et al. Multi-institutional evaluation of upper urinary tract biopsy using backloaded cup biopsy forceps, a nitinol basket, and standard cup biopsy forceps. Urology. 2018;117:89-94.