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Upper Urinary Tract Urothelial Cancer: Difference between revisions

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* UTUC refers to urothelial tumors that originate from the inner lining of the ureter, calyces, or renal pelvis
* UTUC refers to urothelial tumors that originate from the inner lining of the ureter, calyces, or renal pelvis
* '''Panurothelial disease'''
* '''Definition of panurothelial disease:''' '''disease involving the bladder and 2 extravesical sites'''
** '''Defined as a disease involving the bladder and 2 extravesical sites'''
** In males, this could include one or both upper urinary tracts and/or the prostatic urethra
*** In males, this could include one or both upper urinary tracts and/or the prostatic urethra
** In females, this could be the bladder and both upper urinary tracts.
*** In females, this could be the bladder and both upper urinary tracts.
** Low incidence and the lack of prospective studies do not permit absolute conclusions about treatment impact and outcomes
** The low incidence and the lack of prospective studies do not permit absolute conclusions about treatment impact and outcomes


== Epidemiology ==
== Epidemiology ==
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*# '''Non-visualization of the collecting system'''
*# '''Non-visualization of the collecting system'''
*# '''Obstruction'''
*# '''Obstruction'''
* '''<span style="color:#ff0000">Differential diagnosis of a radiolucent filling defect includes (7):</span>'''
* '''<span style="color:#ff0000">Differential diagnosis of filling defect includes (11): [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766367/]</span>'''
*# '''<span style="color:#ff0000">Tumour</span>'''
*# '''<span style="color:#ff0000">Tumour (UTUC, renal cell carcinoma, renal lymphoma, fibroepithelial polyp)</span>'''
*# '''<span style="color:#ff0000">Blood clot</span>'''
*# '''<span style="color:#ff0000">Blood clot</span>'''
*# '''<span style="color:#ff0000">Stones</span>'''; higher HFU than urothelial carcinoma
*# '''<span style="color:#ff0000">Suburothelial hemorrhage</span>'''
*# '''<span style="color:#ff0000">Sloughed papilla</span>'''
*#'''<span style="color:#ff0000">Stones</span>'''; higher HFU than urothelial carcinoma
*# '''<span style="color:#ff0000">Fungus ball</span>'''
*# '''<span style="color:#ff0000">Renal papillary necrosos/sloughed papilla</span>'''
*# '''<span style="color:#ff0000">Overlying bowel gas</span>'''
*# '''<span style="color:#ff0000">Hypertrophied papilla</span>'''
*# '''<span style="color:#ff0000">External compression</span>'''
*#'''<span style="color:#ff0000">Inflammation</span>'''
*#'''<span style="color:#ff0000">Fungus ball</span>'''
*# '''<span style="color:#ff0000">Tuberculosis</span>'''
*#'''<span style="color:#ff0000">Polyureteritis cystics</span>'''
*#'''<span style="color:#ff0000">Retroperitoneal fibrosis</span>'''
* '''Urothelial cancers are enhancing on arterial/early nephrographic phase, dark/filling defect in urographic phase.'''  
* '''Urothelial cancers are enhancing on arterial/early nephrographic phase, dark/filling defect in urographic phase.'''  
*'''Urothelial cancers have more infiltrative features compared to RCC'''
*'''Urothelial cancers have more infiltrative features compared to RCC'''
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=== Special Scenarios ===
=== Special Scenarios ===
'''<span style="color:#ff0000">Positive Upper Tract Urinary Cytology or Carcinoma in Situ</span>'''
* '''<span style="color:#ff0000">Diagnosis and Evaluation</span>'''
** '''<span style="color:#ff0000">First, repeat the cytology to confirm the findings</span>'''
*** '''Any source of inflammation, such as urinary infection or calculus, may produce a false-positive result'''
*** A subsequent cytologic abnormality from the contralateral side during follow-up is not rare in cases of true-positive results from early CIS
** '''<span style="color:#ff0000">Next, radiographic evaluation of the upper tracts, usually with CT urography, and a complete bladder evaluation with cystoscopy</span>'''
*** '''<span style="color:#ff0000">If the bladder evaluation was</span>'''
**** '''<span style="color:#ff0000">Positive for bladder tumour, treat the bladder and follow the voided urinary cytologies.</span>'''
***** If cytology remains positive despite a negative bladder evaluation or after successful treatment of the bladder, proceed to evaluating extravesical sites.
**** '''<span style="color:#ff0000">Negative for bladder tumour, evaluate extravesical sites.</span>'''
***** '''Evaluation of extravesical sites should include <span style="color:#ff0000">selective cytologies from each upper urinary tract,</span>''' ensuring non-contamination of the specimen from the bladder or urethra, '''as well as resection of a representative <span style="color:#ff0000">specimen of the prostatic urethra in men</span>'''.
****** Selective cytologies should preferably be done, along with ureteroscopy, to allow for direct visualization of the upper urinary tracts.
***** '''In cases of unilateral upper tract cytologic abnormalities''' (with normal cystoscopy, pyelography, and bladder biopsies), '''ureteropyeloscopy is indicated as the next step'''.
****** Ureteropyeloscopy allows for direct visualization of small lesions and is superior to retrograde pyelography in the detection of small tumors.
****** '''Biopsy at the time of ureteropyeloscopy should be attempted, if feasible. A persistently abnormal cytology without any visualized lesions may signify CIS'''.
== Prognosis ==


* 5-year overall survival rates:
==== Positive Upper Tract Urinary Cytology ====
** Grade
* '''<span style="color:#ff0000">First, repeat the cytology to confirm the findings</span>'''
*** 1-2: 40-87%
** '''Any source of inflammation, such as urinary infection or calculus, may produce a false-positive result'''
*** 3-4: 0-33%
** A subsequent cytologic abnormality from the contralateral side during follow-up is not rare in cases of true-positive results from early CIS
** Stage
* '''<span style="color:#ff0000">Next, radiographic evaluation of the upper tracts, usually with CT urography, and a complete bladder evaluation with cystoscopy</span>'''
*** Ta, T1, CIS: 60-90%
** '''<span style="color:#ff0000">If the bladder evaluation was</span>'''
*** T2: 43-75%
*** '''<span style="color:#ff0000">Positive for bladder tumour, treat the bladder and follow the voided urinary cytologies.</span>'''
*** T3: 16-33%
**** If cytology remains positive despite a negative bladder evaluation or after successful treatment of the bladder, proceed to evaluating extravesical sites.
*** T4: 0-5%
*** '''<span style="color:#ff0000">Negative for bladder tumour, evaluate extravesical sites.</span>'''
*** N+: 0-4%
**** '''Evaluation of extravesical sites should include <span style="color:#ff0000">selective cytologies from each upper urinary tract,</span>''' ensuring non-contamination of the specimen from the bladder or urethra, '''as well as resection of a representative <span style="color:#ff0000">specimen of the prostatic urethra in men</span>'''.
*** M+: 0%
***** Selective cytologies should preferably be done, along with ureteroscopy, to allow for direct visualization of the upper urinary tracts.
*'''<span style="color:#ff0000">Prognostic factors</span>'''
**** '''In cases of unilateral upper tract cytologic abnormalities''' (with normal cystoscopy, pyelography, and bladder biopsies), '''ureteropyeloscopy is indicated as the next step'''.
**'''<span style="color:#ff0000">Tumour factors</span>'''
***** Ureteropyeloscopy allows for direct visualization of small lesions and is superior to retrograde pyelography in the detection of small tumors.
**# '''<span style="color:#ff0000">Stage</span>'''
***** '''Biopsy at the time of ureteropyeloscopy should be attempted, if feasible. A persistently abnormal cytology without any visualized lesions may signify CIS'''.
**#* '''<span style="color:#ff0000">Most important prognostic factor</span>'''
 
**#** '''<span style="color:#ff0000">Non–organ confined disease (>pT2) is the most significant predictor of the development of metastases</span>'''
**# '''<span style="color:#ff0000">Grade</span>'''
**#* '''<span style="color:#ff0000">High-grade tumours are more likely to:</span>'''
**#*# '''<span style="color:#ff0000">Invade</span>''' into the underlying connective tissue, muscle, and surrounding tissues
**#*# '''<span style="color:#ff0000">Be associated with concomitant CIS</span>'''
**#* '''<span style="color:#ff0000">While there is strong correlation between stage and grade, each independently predicts post-operative recurrence</span>'''
**# '''<span style="color:#ff0000">Architecture</span>'''
**#* '''≈85% of renal pelvic tumors are papillary and the remainder sessile'''
**#* '''<span style="color:#ff0000">Papillary tumors seem to have better outcomes than sessile lesions</span>'''
**#** Invasion of the lamina propria or muscle (stage T1 or T2) occurs in 50% of papillary and in >80% of sessile tumors
**#* '''CIS of the upper tract is associated with higher risk for disease progression''' (similar to bladder cancer) and a likelihood of future development of invasive urothelial cancers.
**# '''Size'''
**#* Tumours > 3-4 cm may be associated with worse survival as well as a higher risk of bladder recurrence
**# '''<span style="color:#ff0000">Location</span>'''
**#* '''<span style="color:#ff0000">Renal pelvic tumours are usually more aggressive than ureteral tumours</span>'''
**#** '''<span style="color:#ff0000">50-60% of renal pelvic tumors are invasive''' into either the lamina propria or muscle, </span>'''in''' '''contrast to most bladder tumors, which are usually non-invasive'''
**#** '''<span style="color:#ff0000">55-75% of ureteral tumors are low grade and low stage, but invasion is still more common than bladder tumors</span>'''
**#** The renal parenchyma may be a barrier, slowing distant spread of stage T3 renal pelvis tumors. In contrast, periureteral tumor extension carries a high risk of early tumor dissemination along the periureteral vascular and lymphatic supply. Improved survival of patients with stage T3 renal pelvis tumors versus ureteral tumors has been reported
**#* '''Conflicting results on whether the location of an upper tract tumor affects prognosis'''
**# '''Multifocality'''
**#* Defined as presence of tumor in ≥2 sites within urothelium
**#* Independent predictor of poor clinical outcome
**# '''Tumour necrosis'''
**#* Conflicting evidence on the influence of tumour necrosis on survival
**# '''Lymph node involvement'''
**#* Although lymphadenectomy is seldom performed for clinically node-negative disease, '''pathologic lymph node status is a strong predictor of post-nephroureterectomy recurrence'''
**# LVI
**#* Associated with worse survival in patients without positive nodes; no association in N+ disease
**# Hydronephrosis
**#* Independently associated with advanced disease stage and poor survival
**# Positive surgical margins
**# Previous or concomitant bladder tumours
** '''Patient factors'''
**# Age
**#* Increasing age associated with worse survival
**# Race
**#* Black non-Hispanic race is associated with increased mortality
** '''Surgical factors'''
**# Lack of post-operative mitomycin C instillation
* '''3 particular forms of UTUC,''' 2 associated with environmental exposure ('''aristolochic acid nephropathy''', which includes Balkan and Chinese herbal nephropathy, as well as those seen in arsenic-endemic regions), '''analgesic abuse, and those associated with Lynch syndrome, have an even higher tendency have multiple and bilateral recurrences than do sporadic tumors'''


== Risk-Stratification of Localized UTUC ==
== Risk-Stratification of Localized UTUC ==
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==== Options (4) ====
==== Options (4) ====
{| class="wikitable"
{| class="wikitable" style="width: 80%; margin: 0 auto;"
!'''<span style="color:#ff0000">Nephron-sparing (3)</span>'''
|-
!'''<span style="color:#ff0000">Non Nephron-sparing (1)</span>'''
| style="width: 40%;" | '''<span style="color:#ff0000">Nephron-sparing (3)</span>'''
| style="width: 40%;" | '''<span style="color:#ff0000">Non Nephron-sparing (1)</span>'''
 
|-
|-
|
|
# '''<span style="color:#ff0000">Endoscopic Ablation/Resection</span>'''
#'''<span style="color:#ff0000">Endoscopic Ablation/Resection</span>'''
##Ureteroscopic
## Ureteroscopic
##Percutaneous
## Percutaneous
#'''<span style="color:#ff0000">Intraluminal Therapy</span>'''
# '''<span style="color:#ff0000">Intraluminal Therapy</span>'''
#'''<span style="color:#ff0000">Segmental Ureterectomy</span>'''
# '''<span style="color:#ff0000">Segmental Ureterectomy</span>'''
|
|
# '''<span style="color:#ff0000">Radical nephroureterectomy with bladder cuff excision</span>'''
#'''<span style="color:#ff0000">Radical nephroureterectomy with bladder cuff excision</span>'''
|}
|}
* Can also be classified as surgical removal (radical nephroureterectomy or segmental ureterectomy) vs. non-surgical removal (endoscopic ablation/resection or intraluminal therapy)
* Can also be classified as surgical removal (radical nephroureterectomy or segmental ureterectomy) vs. non-surgical removal (endoscopic ablation/resection or intraluminal therapy)
*'''Nephron-sparing approaches are associated with high risk of local recurrence'''; '''patients need to be followed vigilantly for disease progression.'''
*'''Nephron-sparing approaches are associated with high risk of local recurrence'''; '''patients need to be followed vigilantly for disease progression.'''
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*'''In patients with LR UTUC with evidence of risk group progression (tumor size, focality, or grade) or when tumor ablation is not feasible,''' further endoscopic-assisted attempts are not recommended. '''surgical resection of all involved sites either by RNU or segmental resection of the ureter should be offered.'''
*'''In patients with LR UTUC with evidence of risk group progression (tumor size, focality, or grade) or when tumor ablation is not feasible,''' further endoscopic-assisted attempts are not recommended. '''surgical resection of all involved sites either by RNU or segmental resection of the ureter should be offered.'''
=====Intraluminal Therapy=====
=====Intraluminal Therapy=====
*'''Used in 3 settings for treatment of UTUC:'''
 
*# '''Adjuvant therapy after endoscopic or organ-sparing therapy (see above)'''
====== Indications (3): ======
*#'''Primary treatment for CIS'''
# '''Adjuvant therapy after endoscopic or organ-sparing therapy'''
*# '''Primary treatment of low-grade UTUC (UGN-101)'''
#'''Primary treatment for CIS (see Special Scenarios)'''
* '''Adjuvant therapy'''
# '''Primary treatment of low-grade UTUC (UGN-101)'''
**'''Pelvicalyceal or intravesical chemotherapy following ablation of UTUC tumors[https://pubmed.ncbi.nlm.nih.gov/37096584/]'''
 
***Principle of an immediate instillation of intravesical or pyelocaliceal (upper tract) chemotherapy at the time of endoscopic tumor ablation for UTUC is undertaken by extrapolation of the data supporting immediate instillation of intravesical chemotherapy at the time of transurethral resection of a bladder tumor
====== Adjuvant therapy ======
***Options: thiotepa, mitomycin
*'''Pelvicalyceal or intravesical chemotherapy following ablation of UTUC tumors[https://pubmed.ncbi.nlm.nih.gov/37096584/]'''
**Principle of an immediate instillation of intravesical or pyelocaliceal (upper tract) chemotherapy at the time of endoscopic tumor ablation for UTUC is undertaken by extrapolation of the data supporting immediate instillation of intravesical chemotherapy at the time of transurethral resection of a bladder tumor
**Options: thiotepa, mitomycin
**'''Indications'''
*** '''Considered optional'''
** Technique
***Prior to administration, must confirm that there is no perforation of the bladder or upper tract
***Approaches (3)
***#Antegrade perfusion by nephrostomy tube
***#Retrograde perfusion via ureteral catheter
***#Bladder instillation by transurethral catheter with reflux via a double J ureteral stent.
***#*In the third scenario, a cystogram and demonstration of adequate reflux of contrast into the pyelocaliceal system is recommended.
*'''Immunotherapy'''
**'''Pelvicalyceal BCG[https://pubmed.ncbi.nlm.nih.gov/37096584/]'''
***'''Indications'''
***'''Indications'''
**** '''Considered optional'''
****'''May be offered to patients with HR favorable UTUC after complete tumor ablation or patients with upper tract carcinoma in situ (CIS).'''
*** Technique
****'''Imperative indications'''
****Prior to administration, must confirm that there is no perforation of the bladder or upper tract
****#'''Solitary kidney status'''
****Approaches (3)
****# '''Bilateral UTUC'''
****#Antegrade perfusion by nephrostomy tube
****#'''Risk of progression to end-stage renal disease'''
****#Retrograde perfusion via ureteral catheter
***Consists of a 6-week induction course of BCG
****#Bladder instillation by transurethral catheter with reflux via a double J ureteral stent.
* '''Outcomes'''
****#*In the third scenario, a cystogram and demonstration of adequate reflux of contrast into the pyelocaliceal system is recommended.
**'''<span style="color:#ff00ff">Systematic review and meta-analysis (2019)</span>'''
**'''Immunotherapy'''
*** Inclusion criteria: studies evaluating patients with upper tract urothelial carcinoma receiving instillation treatment as adjuvant/curative therapy for pTa/pT1 and CIS, respectively.
***'''Pelvicalyceal BCG[https://pubmed.ncbi.nlm.nih.gov/37096584/]'''
*** Studies with ≥10 participants included in quantitative analyses
****'''Indications'''
*** Results
*****'''May be offered to patients with HR favorable UTUC after complete tumor ablation or patients with upper tract carcinoma in situ (CIS).'''
**** Included 212 patients from 12 studies of patients that underwent endoscopic laser ablation and instillation therapy for Ta/T1 UTUC
*****'''Imperative indications'''
**** Recurrence-free survival: 40%
*****#'''Solitary kidney status'''
***** Similar to recurrence-free survival with observation after nephron-sparing surgery
*****# '''Bilateral UTUC'''
**** Cancer-specific survival: 94%
*****#'''Risk of progression to end-stage renal disease'''
**** Overall survival: 71%
****Consists of a 6-week induction course of BCG
**** No difference in survival based on approach (antegrade, retrograde, or combined) or drug (MMC vs. BCG)
** '''Outcomes'''
*** [https://pubmed.ncbi.nlm.nih.gov/30846387/ Foerster, Beat, et al. "Endocavitary treatment for upper tract urothelial carcinoma: a meta-analysis of the current literature." ''Urologic Oncology: Seminars and Original Investigations''. Vol. 37. No. 7. Elsevier, 2019.]
***'''<span style="color:#ff00ff">Systematic review and meta-analysis (2019)</span>'''
* '''Adverse events'''
**** Inclusion criteria: studies evaluating patients with upper tract urothelial carcinoma receiving instillation treatment as adjuvant/curative therapy for pTa/pT1 and CIS, respectively.
**'''Most common complication of intraluminal/instillation therapy is bacterial sepsis'''
**** Studies with ≥10 participants included in quantitative analyses
**** Results
***** Included 212 patients from 12 studies of patients that underwent endoscopic laser ablation and instillation therapy for Ta/T1 UTUC
***** Recurrence-free survival: 40%
****** Similar to recurrence-free survival with observation after nephron-sparing surgery
***** Cancer-specific survival: 94%
***** Overall survival: 71%
***** No difference in survival based on approach (antegrade, retrograde, or combined) or drug (MMC vs. BCG)
**** [https://pubmed.ncbi.nlm.nih.gov/30846387/ Foerster, Beat, et al. "Endocavitary treatment for upper tract urothelial carcinoma: a meta-analysis of the current literature." ''Urologic Oncology: Seminars and Original Investigations''. Vol. 37. No. 7. Elsevier, 2019.]
** '''Adverse events'''
***'''Most common complication of intraluminal/instillation therapy is bacterial sepsis'''
*'''<span style="color:#ff0000">CIS of the Upper Urinary Tracts</span>'''
** '''In most cases, the diagnosis is one of exclusion wherein there is a persistent positive selective cytology in the absence of any ureteroscopic or radiographic findings.'''
*** The diagnosis of CIS of the upper urinary tracts difficult because of the inability to evaluate the urothelium of the upper tracts with adequate tissue samples
** '''Management'''
*** '''Not well established'''
*** '''<span style="color:#ff0000">Current approaches for presumed upper tract CIS include topical immunotherapy or chemotherapy'''
**** '''Most experience is from use of BCG via a nephrostomy tube for primary treatment of CIS.'''
***** '''<span style="color:#ff00ff">Systematic review and meta-analysis evaluating intraluminal therapy for UTUC (2019)</span>'''
****** Inclusion criteria: studies evaluating patients with upper tract urothelial carcinoma receiving instillation treatment as adjuvant/curative therapy for pTa/pT1 and CIS, respectively.
****** Studies with ≥10 participants included in quantitative analyses
****** Results
******* Included 226 patients from 15 studies of patients that underwent BCG instillation for CIS
******* Recurrence-free survival: 84%
******* Cancer-specific survival: 34%
******* Overall survival: 16%
******* No difference in survival based on approach (antegrade, retrograde, or combined) or drug (MMC vs. BCG)
****** Foerster, Beat, et al. "Endocavitary treatment for upper tract urothelial carcinoma: a meta-analysis of the current literature." ''Urologic Oncology: Seminars and Original Investigations''. Vol. 37. No. 7. Elsevier, 2019.
**** Historically, '''<span style="color:#ff0000">radical nephroureterectomy</span>''' was performed for a unilateral cytologic abnormality of the upper tract to eliminate presumed CIS. This practice '''<span style="color:#ff0000">is not recommended</span>''' in the absence of any histologic, radiographic, or endoscopic finding '''owing to the limitations of cytology alone with false-positive results and the high risk for bilateral disease in the future'''
**** '''Observation is also not appropriate without further evaluation given the repeated abnormal cytologies.'''
** Management of CIS of ureteral margins during radical cystectomy is controversial


* '''<span style="color:#ff0000">UGN-101</span>''' (also known as Mitogel, Jelmyto)
====== <span style="color:#ff0000">Primary treatment for low-grade UTUC</span> ======
** Effectiveness of intraluminal therapy has been limited by inadequate exposure to urothelium from fluid preparations due to rapid drainage from (2)
*Effectiveness of intraluminal therapy has been limited by inadequate exposure to urothelium from fluid preparations due to rapid drainage from (2)
***No storage capacity of UTUC (unlike bladder)
**No storage capacity of UTUC (unlike bladder)
***Ureteral and pelvic peristalsis
**Ureteral and pelvic peristalsis
**Potential solution is to use reverse thermosensitive polymers, which are liquid at room temperature and convert to a gel at body temperature, resulting in increased dwell time
*Potential solution is to use reverse thermosensitive polymers, which are liquid at room temperature and convert to a gel at body temperature, resulting in increased dwell time
**'''<span style="color:#ff00ff">OLYMPUS (Lancet Onc 2020</span>''')
*'''<span style="color:#ff0000">UGN-101</span>'''
**'''UGN-101 = MMC + reverse thermosensitive polymer'''
***Also known as Mitogel, Jelmyto
**'''<span style="color:#ff00ff">OLYMPUS (Lancet Oncology 2020</span>''')
*** Objective: evaluate the safety and activity of UGN-101 to treat primary and recurrent low-grade UTUC.
*** Objective: evaluate the safety and activity of UGN-101 to treat primary and recurrent low-grade UTUC.
*** '''Design: open-label, single-arm, phase 3 trial'''
*** '''Design: open-label, single-arm, phase 3 trial'''
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****** 20% renal dysfunction
****** 20% renal dysfunction
*** [https://pubmed.ncbi.nlm.nih.gov/32631491/ Kleinmann, Nir, et al.] "Primary chemoablation of low-grade upper tract urothelial carcinoma using UGN-101, a mitomycin-containing reverse thermal gel (OLYMPUS): an open-label, single-arm, phase 3 trial." ''The lancet oncology'' 21.6 (2020): 776-785.
*** [https://pubmed.ncbi.nlm.nih.gov/32631491/ Kleinmann, Nir, et al.] "Primary chemoablation of low-grade upper tract urothelial carcinoma using UGN-101, a mitomycin-containing reverse thermal gel (OLYMPUS): an open-label, single-arm, phase 3 trial." ''The lancet oncology'' 21.6 (2020): 776-785.
*'''Technique'''
**'''Approaches:'''
**'''Approaches:'''
***'''Antegrade via percutaneous nephrostomy'''
***'''Antegrade via percutaneous nephrostomy'''
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**** '''Suboptimal because the drug often does not reach the renal pelvis'''
**** '''Suboptimal because the drug often does not reach the renal pelvis'''
*** Both the antegrade and retrograde approach can be dangerous due to possible ureteric obstruction and consecutive pyelovenous influx during instillation/perfusion.
*** Both the antegrade and retrograde approach can be dangerous due to possible ureteric obstruction and consecutive pyelovenous influx during instillation/perfusion.
=====Segmental ureterectomy=====
=====Segmental Ureterectomy=====
*'''Options'''
*'''Reasonable alternative to RNU for well-selected patients'''
**'''<span style="color:#ff0000">Segmental ureterectomy with ureteroureterostomy</span>'''
 
*** '''<span style="color:#ff0000">Small, unifocal tumors (typically 1 cm or smaller) tumors isolated to a short segment of the proximal or mid-ureter requiring resection of ≤2 cm or less of ureteral length to allow for primary ureteroureterostomy.</span>'''
====== Options ======
****Longer sections of ureteral involvement and resection may require more complex reconstruction techniques when kidney sparing is desired.
*'''<span style="color:#ff0000">Segmental ureterectomy with ureteroureterostomy</span>'''
**'''<span style="color:#ff0000">Distal ureterectomy with ureteral reimplant</span>'''
** '''<span style="color:#ff0000">Small, unifocal tumors (typically 1 cm or smaller) tumors isolated to a short segment of the proximal or mid-ureter requiring resection of ≤2 cm or less of ureteral length to allow for primary ureteroureterostomy.</span>'''
***'''<span style="color:#ff0000">Preferred treatment for surgically eligible patients with HR and unfavorable LR cancers endoscopically confirmed as confined to the lower ureter in a functional renal unit</span>'''
***Longer sections of ureteral involvement and resection may require more complex reconstruction techniques when kidney sparing is desired.
****Tumor ablation considered alternative options to the gold-standard of extirpative resection
*'''<span style="color:#ff0000">Distal ureterectomy with ureteral reimplant</span>'''
*****Tumor ablation may yield less optimal results and require multiple additional procedures
**'''<span style="color:#ff0000">Preferred treatment for surgically eligible patients with HR and unfavorable LR cancers endoscopically confirmed as confined to the lower ureter in a functional renal unit</span>'''
***Most favorable candidates for distal ureterectomy are patients who
***Tumor ablation considered alternative options to the gold-standard of extirpative resection
****Have ureteral tumors in the lower third of the ureter
****Tumor ablation may yield less optimal results and require multiple additional procedures
****Sufficiently mobile bladder with capacity to facilitate reimplantation with or without reconfiguration of the bladder to facilitate a tension-free anastomosis (i.e., Boari flap or psoas hitch maneuver).
**Most favorable candidates for distal ureterectomy are patients who
*'''Reasonable alternatives to RNU for well-selected patients'''
***Have ureteral tumors in the lower third of the ureter
*'''Principles'''
***Sufficiently mobile bladder with capacity to facilitate reimplantation with or without reconfiguration of the bladder to facilitate a tension-free anastomosis (i.e., Boari flap or psoas hitch maneuver).
*#'''Patient counseling''' to describe techniques, potential requirements for urinary reconstruction and associated complications including the potential impact on postoperative bladder function.
 
*#'''Preoperative endoscopic assessment''' to evaluate sites of involvement and proximal extent of disease.
====== Principles ======
*#'''Preoperative assessment of bladder capacity''' and function in cases where more extensive reconstruction such as a Boari flap are anticipated to permit a tension free ureterovesical anastomosis or the use of bowel segments.
#'''Patient counseling''' to describe techniques, potential requirements for urinary reconstruction and associated complications including the potential impact on postoperative bladder function.
*#'''Intraoperative pathologic assessment''' (i.e., frozen sections) of proximal and distal margins to ensure complete resection with negative margins.
#'''Preoperative endoscopic assessment''' to evaluate sites of involvement and proximal extent of disease.
*#Reasonable attempts to '''avoid of spillage of urine''' into the surgical field.
#'''Preoperative assessment of bladder capacity''' and function in cases where more extensive reconstruction such as a Boari flap are anticipated to permit a tension free ureterovesical anastomosis or the use of bowel segments.
*# '''Watertight, tension free closure''' to facilitate functional healing and avoid urine leak (of urine potentially contaminated with malignant cells).
#'''Intraoperative pathologic assessment''' (i.e., frozen sections) of proximal and distal margins to ensure complete resection with negative margins.
*'''When performing NU or distal ureterectomy, the entire distal ureter including the intramural ureteral tunnel and ureteral orifice should be excised, and the urinary tract should be closed in a watertight fashion.'''
#Reasonable attempts to '''avoid of spillage of urine''' into the surgical field.
**The resultant hiatus in the bladder in the location of the excised ureteral orifice with or without the bladder cuff can be closed formally in a watertight fashion in one or more layers
# '''Watertight, tension free closure''' to facilitate functional healing and avoid urine leak (of urine potentially contaminated with malignant cells).
***A formal BCE with watertight closure of the bladder cuff should be performed to
 
***#Avoid urinary extravasation from the bladder
====== Outcomes ======
***#Facilitate more rapid catheter removal
***#Permit instillation of intravesical adjuvant chemotherapy in the perioperative setting
***Delayed closure by secondary intension in a decompressed bladder without formal bladder closure has also been described.
'''Outcomes'''
* '''<span style="color:#ff00ff">Systematic review and meta-analysis comparing segmental resection to radical nephroureterectomy (2020)</span>'''
* '''<span style="color:#ff00ff">Systematic review and meta-analysis comparing segmental resection to radical nephroureterectomy (2020)</span>'''
** Results:
** Results:
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**** OS: no significant difference
**** OS: no significant difference
*** Veccia, Alessandro, et al."Segmental ureterectomy for upper tract urothelial carcinoma: a systematic review and meta-analysis of comparative studies." ''Clinical genitourinary cancer'' 18.1 (2020): e10-e20.
*** Veccia, Alessandro, et al."Segmental ureterectomy for upper tract urothelial carcinoma: a systematic review and meta-analysis of comparative studies." ''Clinical genitourinary cancer'' 18.1 (2020): e10-e20.
* The documented risk of wound implantation by tumor is low after open segmental ureterectomy if simple precautions are followed to minimize spillage
* Segmental ureterectomy of the proximal two-thirds of ureter is associated with higher failure rates than for the distal ureter.
* Segmental ureterectomy of the proximal two-thirds of ureter is associated with higher failure rates than for the distal ureter.


* Technique
====== Technique ======
** See Segmental Ureterectomy Chapter Notes for technical aspects
* Risk of wound implantation by tumor is low after open segmental ureterectomy if simple precautions are followed to minimize spillage
*See Segmental Ureterectomy Chapter Notes for technical aspects
*'''When performing NU or distal ureterectomy, the entire distal ureter including the intramural ureteral tunnel and ureteral orifice should be excised, and the urinary tract should be closed in a watertight fashion.'''
**The resultant hiatus in the bladder in the location of the excised ureteral orifice with or without the bladder cuff can be closed formally in a watertight fashion in one or more layers
***A formal BCE with watertight closure of the bladder cuff should be performed to
***#Avoid urinary extravasation from the bladder
***#Facilitate more rapid catheter removal
***#Permit instillation of intravesical adjuvant chemotherapy in the perioperative setting
***Delayed closure by secondary intension in a decompressed bladder without formal bladder closure has also been described.
=====Radical nephroureterectomy with bladder cuff excision=====
=====Radical nephroureterectomy with bladder cuff excision=====


*'''Principles[https://pubmed.ncbi.nlm.nih.gov/37096584/]'''
====== Principles[https://pubmed.ncbi.nlm.nih.gov/37096584/] ======
*#'''Complete excision of ipsilateral upper tract urothelium''', including the intramural portion of the ureter and ureteral orifice with negative margins
#'''Complete excision of ipsilateral upper tract urothelium''', including the intramural portion of the ureter and ureteral orifice with negative margins
*##Specimen should be removed en bloc whenever technically feasible
##Specimen should be removed en bloc whenever technically feasible
*# '''Avoidance of urinary spillage,''' such as by early low ligation of the ureter, to minimize the risk of seeding urothelial cancer outside the urinary tract.
# '''Avoidance of urinary spillage,''' such as by early low ligation of the ureter, to minimize the risk of seeding urothelial cancer outside the urinary tract.
 
====== Outcomes ======
*Largely dependent on clinicopathologic characteristics.
*'''<span style="color:#ff00ff">Systematic review and meta-analysis comparing nephron-sparing approach to radical nephroureterectomy (2016)</span>'''
** Primary outcome: cancer-specific survival
** Results
*** Included 22 studies published between 1999 and 2015
**** No RCTs comparing nephron-sparing approach and nephroureterectomy
*** High risk of bias across all domains analysed, limiting interpretation of comparisons
*** Segemental ureterectomy vs. RNU (10 studies): no significant difference in cancer-specific survival
*** Endoscopic vs. RNU
**** URS vs. RNU (5 studies): no significant difference in cancer-specific survival
***** Grade-based subgroup analyses found decreased cancer-specific survival in patients undergoing URS for high-grade disease
**** Percutaneous resection vs. RNU (2 studies): conflicting findings
** Seisen, Thomas, et al."Oncologic outcomes of kidney-sparing surgery versus radical nephroureterectomy for upper tract urothelial carcinoma: a systematic review by the EAU non-muscle invasive bladder cancer guidelines panel." ''European urology'' 70.6 (2016): 1052-1068.
 
====== Technique ======
*See Nephroureterectomy Chapter Notes for technical aspects
*'''Approach[https://pubmed.ncbi.nlm.nih.gov/37096584/]'''
*'''Approach[https://pubmed.ncbi.nlm.nih.gov/37096584/]'''
**Open, robotic, and laparoscopic approaches are suitable
**Open, robotic, and laparoscopic approaches are suitable
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**Worse local and metastatic recurrence rates with associated decreased CSS and OS for patients who did not receive complete BCE.
**Worse local and metastatic recurrence rates with associated decreased CSS and OS for patients who did not receive complete BCE.
** Approach
** Approach
***Extravesical or transvesical l (e.g., midline cystotomy)
***Extravesical or transvesical (e.g., midline cystotomy)
***Open, minimally invasive or transurethral endoscopic techniques.
***Open, minimally invasive or transurethral endoscopic techniques.
****Transurethral endoscopic approaches are associated with higher recurrence rates in the bladder and may limit the ability to utilize post-NU intravesical therapies if the bladder is not fully closed
****Transurethral endoscopic approaches are associated with higher recurrence rates in the bladder and may limit the ability to utilize post-NU intravesical therapies if the bladder is not fully closed
*'''Complication rates following RNU'''
 
**Range from 15% to 50%
====== Adverse events ======
** '''30-day mortality risk of 1%'''
*Range from 15% to 50%
*Outcomes largely dependent on clinicopathologic characteristics.
* '''30-day mortality risk of 1%'''
**'''<span style="color:#ff00ff">Systematic review and meta-analysis comparing nephron-sparing approach to radical nephroureterectomy (2016)</span>'''
*** Primary outcome: cancer-specific survival
*** Results
**** Included 22 studies published between 1999 and 2015
***** No RCTs comparing nephron-sparing approach and nephroureterectomy
**** High risk of bias across all domains analysed, limiting interpretation of comparisons
**** Segemental ureterectomy vs. RNU (10 studies): no significant difference in cancer-specific survival
**** Endoscopic vs. RNU
***** URS vs. RNU (5 studies): no significant difference in cancer-specific survival
****** Grade-based subgroup analyses found decreased cancer-specific survival in patients undergoing URS for high-grade disease
***** Percutaneous resection vs. RNU (2 studies): conflicting findings
*** Seisen, Thomas, et al."Oncologic outcomes of kidney-sparing surgery versus radical nephroureterectomy for upper tract urothelial carcinoma: a systematic review by the EAU non-muscle invasive bladder cancer guidelines panel." ''European urology'' 70.6 (2016): 1052-1068.
* See Nephroureterectomy Chapter Notes for technical aspects


====Treatment Selection====
====Treatment Selection====


* '''Based on risk stratification'''
* '''Based on risk stratification (see above)'''


=====UrologySchool.com Summary=====
=====UrologySchool.com Summary=====
 
'''AUA'''
====== AUA ======
*'''<span style="color:#ff0000">If low-risk</span>'''
*'''<span style="color:#ff0000">If low-risk</span>'''
**'''<span style="color:#ff0000">Favorable</span>'''
**'''<span style="color:#ff0000">Favorable</span>'''
***'''<span style="color:#ff0000">Tumor ablation (preferred)</span>'''
***'''<span style="color:#ff0000">Tumor ablation (preferred, when technically feasible)</span>'''
****Observational studies suggest similar cancer-specific survival, similar complication rates, and improved renal function outcomes with endoscopic ablation, compared to nephroureterectomy
**'''<span style="color:#ff0000">Unfavorable</span>'''
**'''<span style="color:#ff0000">Unfavorable</span>'''
***'''<span style="color:#ff0000">Tumor ablation (optional)</span>'''
***'''<span style="color:#ff0000">Tumor ablation (optional for patients with low-volume tumors or cannot undergo RNU)</span>'''
***'''<span style="color:#ff0000">Surgical removal (radical nephroureterectomy or segmental ureterectomy)</span>'''
***'''<span style="color:#ff0000">Surgical removal (radical nephroureterectomy or segmental ureterectomy)</span>'''
**'''<span style="color:#ff0000">If low-risk and complete endoscopic ablation not feasible, chemoablation (in-situ tissue destruction) with mitomycin containing reverse thermal gel can be a treatment alternative</span>'''
**'''<span style="color:#ff0000">If low-risk and complete endoscopic ablation not feasible, chemoablation (in-situ tissue destruction) with mitomycin containing reverse thermal gel can be a treatment alternative</span>'''
*'''<span style="color:#ff0000">If high-risk</span>'''
*'''<span style="color:#ff0000">If high-risk</span>'''
** '''<span style="color:#ff0000">Favorable</span>'''
** '''<span style="color:#ff0000">RNU with complete bladder cuff excision and lymphadenectomy is the standard of care for patients with HR UTUC.</span>'''
***'''<span style="color:#ff0000">Surgical removal</span>'''
**'''<span style="color:#ff0000">Favorable</span>'''
***'''<span style="color:#ff0000">Tumor ablation (optional)</span>'''
***'''<span style="color:#ff0000">Surgical removal (preferred)</span>'''
***'''<span style="color:#ff0000">Tumor ablation (optional for patients with low-volume tumors or cannot undergo RNU)</span>'''
****'''<span style="color:#ff0000">Select patients who have low-volume tumors or cannot undergo RNU</span>'''
****'''<span style="color:#ff0000">Select patients who have low-volume tumors or cannot undergo RNU</span>'''
**'''<span style="color:#ff0000">Unfavorable</span>'''
**'''<span style="color:#ff0000">Unfavorable</span>'''
***'''<span style="color:#ff0000">Surgical removal</span>'''
***'''<span style="color:#ff0000">Surgical removal (preferred)</span>'''
**'''<span style="color:#ff0000">For surgically eligible patients with HR and unfavorable LR cancers endoscopically confirmed as confined to the lower ureter in a functional renal unit, distal ureterectomy with ureteral reimplant is the preferred treatment</span>'''  
**'''<span style="color:#ff0000">For surgically eligible patients with HR and unfavorable LR cancers endoscopically confirmed as confined to the lower ureter in a functional renal unit, distal ureterectomy with ureteral reimplant is the preferred treatment</span>'''  
===== <span style="color:#ff0000">Endoscopic Treatment </span>=====
====== <span style="color:#ff0000">Indications</span> ======
*'''AUA'''
**'''<span style="color:#ff0000">Preferred</span>'''
***'''<span style="color:#ff0000">Initial management for LR favorable UTUC, when technically feasible</span>'''
****Observational studies suggest similar cancer-specific survival, similar complication rates, and improved renal function outcomes with endoscopic ablation, compared to nephroureterectomy
**'''<span style="color:#ff0000">Optional</span>'''
***'''<span style="color:#ff0000">Initial management for LR unfavorable UTUC and select patients with HR favorable disease who have low-volume tumors or cannot undergo RNU</span>'''
**'''<span style="color:#ff0000">If low-risk and complete endoscopic ablation not feasible, chemoablation (in-situ tissue destruction) with mitomycin containing reverse thermal gel can be a treatment alternative</span>'''
***High risk of ureteric stenosis with instillation of mitomycin containing reverse thermal gel
===== Surgical Removal =====
======Indications======
====== AUA ======
*'''Preferred'''
**'''Surgically eligible patients with HR UTUC'''
======Approaches======
#'''Radical nephroureterectomy with complete bladder cuff excision (BCE)'''
#*'''RNU with complete bladder cuff excision and lymphadenectomy is the standard of care for patients with HR UTUC.'''
#'''Segmental ureterectomy'''
==== Patient counseling[https://pubmed.ncbi.nlm.nih.gov/37096584/] ====
==== Patient counseling[https://pubmed.ncbi.nlm.nih.gov/37096584/] ====
*'''<span style="color:#ff0000">Discuss and facilitate smoking cessation, if applicable,</span> with patients at the time of diagnosis and treatment.'''
*'''<span style="color:#ff0000">Discuss and facilitate smoking cessation, if applicable,</span> with patients at the time of diagnosis and treatment.'''
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*##*In patients with sufficiently poor CKD in which NU could precipitate ESRD, a post operative plan for dialysis in conjunction with nephrology colleagues should be in place preoperatively including plans for dialysis access. Referral to nephrology for detailed evaluation and recommendations for perioperative management is warranted in such cases
*##*In patients with sufficiently poor CKD in which NU could precipitate ESRD, a post operative plan for dialysis in conjunction with nephrology colleagues should be in place preoperatively including plans for dialysis access. Referral to nephrology for detailed evaluation and recommendations for perioperative management is warranted in such cases
*##'''<span style="color:#ff0000">Side effects from neoadjuvant and adjuvant therapies.</span>'''  
*##'''<span style="color:#ff0000">Side effects from neoadjuvant and adjuvant therapies.</span>'''  
=====Lymph node dissection=====
====Lymph Node Dissection====
 
* No RCTs to evaluate the effect of LND on oncologic outcomes in patients undergoing NU or SU
* '''<span style="color:#ff0000">Indications</span>'''
** '''AUA'''
*** '''<span style="color:#ff0000">Recommended (1): HR UTUC</span>'''
**** Sufficient non-randomized evidence to suggest an oncologic benefit to LND at the time of NU for patients with “HR” stratification by guidelines
*** '''<span style="color:#ff0000">Optional (1): LR UTUC</span>'''
**** Limited evidence exists to support a beneficial role for LND at time of NU or ureterectomy among patients with LR UTUC
*'''Template based on tumor collection'''
**'''Pyelocaliceal system: lymph nodes of the ipsilateral great vessel extending from the renal hilum to at least the inferior mesenteric artery.'''
**'''Proximal 2/3 of the ureter: lymph nodes of the ipsilateral great vessel extending from the renal hilum to the aortic bifurcation.'''
**'''Distal 1/3 of the ureter: ipsilateral pelvic LND to include at minimum the obturator and external iliac nodal packets.'''
**Internal and common iliac nodal packets may be removed in the appropriate clinical setting.
**Limited data suggest cranial migration of lymph node metastases to the ipsilateral great vessels such that higher dissection may be considered in the appropriate clinical setting and per clinician judgement


====== AUA ======
==== Neoadjuvant/Adjuvant Therapy After Complete Excision====
*'''<span style="color:#ff0000">If HR UTUC, LND recommended</span>'''
=====Adjuvant intravesical chemotherapy=====
**No RCTs to evaluate the effect of LND on oncologic outcomes in patients undergoing NU or SU
**Sufficient non-randomized evidence to suggest an oncologic benefit to LND at the time of NU for patients with “HR” stratification by guidelines
**'''Recommended minimal templates in non-metastatic disease'''
***'''Tumors in the pyelocaliceal system: lymph nodes of the ipsilateral great vessel extending from the renal hilum to at least the inferior mesenteric artery.'''
***'''Tumors in the proximal 2/3 of the ureter: lymph nodes of the ipsilateral great vessel extending from the renal hilum to the aortic bifurcation.'''
***'''Tumors in the distal 1/3 of the ureter: ipsilateral pelvic LND to include at minimum the obturator and external iliac nodal packets.'''
***Internal and common iliac nodal packets may be removed in the appropriate clinical setting.
***Limited data suggest cranial migration of lymph node metastases to the ipsilateral great vessels such that higher dissection may be considered in the appropriate clinical setting and per clinician judgement
*'''<span style="color:#ff0000">If LR UTUC, LND optional</span>'''
**Limited evidence exists to support a beneficial role for LND at time of NU or ureterectomy among patients with LR UTUC
*Template depends on tumor location and side[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4896731/]
===== Neoadjuvant/Adjuvant Therapy After Complete Excision=====
======Adjuvant intravesical chemotherapy======
*'''<span style="color:#ff0000">In patients undergoing RNU or SU (including distal ureterectomy) for UTUC, a single dose of perioperative intravesical chemotherapy should be administered in eligible patients to reduce the risk of bladder recurrence.[https://pubmed.ncbi.nlm.nih.gov/37096584/]</span>'''
*'''<span style="color:#ff0000">In patients undergoing RNU or SU (including distal ureterectomy) for UTUC, a single dose of perioperative intravesical chemotherapy should be administered in eligible patients to reduce the risk of bladder recurrence.[https://pubmed.ncbi.nlm.nih.gov/37096584/]</span>'''
**The exact timing of therapy has varied including instilling intravesical chemotherapy at the time of catheter removal (ODMIT-C trial), while other retrospective series reported instillation during surgery or up to 48 hours postoperatively.
**The exact timing of therapy has varied including instilling intravesical chemotherapy at the time of catheter removal (ODMIT-C trial), while other retrospective series reported instillation during surgery or up to 48 hours postoperatively.
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*** Little data to support one intravesical chemotherapeutic over another.
*** Little data to support one intravesical chemotherapeutic over another.
****Many use gemcitabine over mitomycin due to risks of chemical peritonitis with extravesical extravasation of MMC
****Many use gemcitabine over mitomycin due to risks of chemical peritonitis with extravesical extravasation of MMC
======Systemic Therapy======
=====Systemic Therapy=====


* '''Neoadjuvant'''  
* '''Neoadjuvant'''  
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**** Retrospective studies suggest that there may be a role for combined radiation-chemotherapy regimens in patients with advanced disease with adverse features
**** Retrospective studies suggest that there may be a role for combined radiation-chemotherapy regimens in patients with advanced disease with adverse features
====Special scenarios====
====Special scenarios====
===== CIS of the Upper Urinary Tracts =====
* '''In most cases, the diagnosis is one of exclusion wherein there is a persistent positive selective cytology in the absence of any ureteroscopic or radiographic findings.'''
** The diagnosis of CIS of the upper urinary tracts difficult because of the inability to evaluate the urothelium of the upper tracts with adequate tissue samples
* '''Management'''
** '''Not well established'''
** '''<span style="color:#ff0000">Current approaches for presumed upper tract CIS include topical immunotherapy or chemotherapy'''
*** '''Most experience is from use of BCG via a nephrostomy tube for primary treatment of CIS.'''
**** '''<span style="color:#ff00ff">Systematic review and meta-analysis evaluating intraluminal therapy for UTUC (2019)</span>'''
***** Inclusion criteria: studies evaluating patients with upper tract urothelial carcinoma receiving instillation treatment as adjuvant/curative therapy for pTa/pT1 and CIS, respectively.
***** Studies with ≥10 participants included in quantitative analyses
***** Results
****** Included 226 patients from 15 studies of patients that underwent BCG instillation for CIS
****** Recurrence-free survival: 84%
****** Cancer-specific survival: 34%
****** Overall survival: 16%
****** No difference in survival based on approach (antegrade, retrograde, or combined) or drug (MMC vs. BCG)
***** Foerster, Beat, et al. "Endocavitary treatment for upper tract urothelial carcinoma: a meta-analysis of the current literature." ''Urologic Oncology: Seminars and Original Investigations''. Vol. 37. No. 7. Elsevier, 2019.
*** Historically, '''<span style="color:#ff0000">radical nephroureterectomy</span>''' was performed for a unilateral cytologic abnormality of the upper tract to eliminate presumed CIS. This practice '''<span style="color:#ff0000">is not recommended</span>''' in the absence of any histologic, radiographic, or endoscopic finding '''owing to the limitations of cytology alone with false-positive results and the high risk for bilateral disease in the future'''
*** '''Observation is also not appropriate without further evaluation given the repeated abnormal cytologies.'''
* Management of CIS of ureteral margins during radical cystectomy is controversial
===== CIS limited to the region within the ureteral orifice =====
*Topical therapies such as BCG along with refluxing ureteral stenting that has been used for in cases of CIS near the ureterovesical junction or transurethral resection of the transmural portion of the ureter for very distal tumors, as an extension of bladder resection procedures, when tumor is limited to the region inside the ureteral orifice and not beyond the bladder wall, thus anatomically managed as bladder cancer


===== Watchful waiting or surveillance =====
===== Watchful waiting or surveillance =====
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*Discussion of treatment related risks including perioperative mortality may lead to a shared decision to proceed with active surveillance (whereby periodic assessments such as imaging or limited endoscopic assessment are performed) or watchful waiting/expectant management, where interventions are limited to palliation or awaiting symptomatic progression – especially in those with very limited life expectancy.
*Discussion of treatment related risks including perioperative mortality may lead to a shared decision to proceed with active surveillance (whereby periodic assessments such as imaging or limited endoscopic assessment are performed) or watchful waiting/expectant management, where interventions are limited to palliation or awaiting symptomatic progression – especially in those with very limited life expectancy.
**In such cases, patients and family should be counseled and prepared for disease-related events such as bleeding, obstruction, infection, and pain with options for palliation that may be limited.
**In such cases, patients and family should be counseled and prepared for disease-related events such as bleeding, obstruction, infection, and pain with options for palliation that may be limited.
===== CIS limited to the region within the ureteral orifice=====
*Topical therapies such as BCG along with refluxing ureteral stenting that has been used for in cases of CIS near the ureterovesical junction or transurethral resection of the transmural portion of the ureter for very distal tumors, as an extension of bladder resection procedures, when tumor is limited to the region inside the ureteral orifice and not beyond the bladder wall, thus anatomically managed as bladder cancer
=== Advanced disease ===
=== Advanced disease ===
==== Clinical, regional node-positive (N+)====
==== Clinical, regional node-positive (N+)====
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**Formulating alternative care options should be approached with multi-disciplinary input with a focus on realistic goals of care such as providing means of local control for functional preservation (e.g., renal function) and palliation (e.g., bleeding, infection)
**Formulating alternative care options should be approached with multi-disciplinary input with a focus on realistic goals of care such as providing means of local control for functional preservation (e.g., renal function) and palliation (e.g., bleeding, infection)
**Multi-modal approaches include combination of endoscopic management to maintain upper and lower tract function (e.g., stents, nephrostomies, ablation for bleeding and local control) in addition to systemic treatment options if available. Rarely, radiation, angioembolization, or percutaneous ablation for palliation of bleeding can be offered
**Multi-modal approaches include combination of endoscopic management to maintain upper and lower tract function (e.g., stents, nephrostomies, ablation for bleeding and local control) in addition to systemic treatment options if available. Rarely, radiation, angioembolization, or percutaneous ablation for palliation of bleeding can be offered
== Prognosis ==
* 5-year overall survival rates:
** Grade
*** 1-2: 40-87%
*** 3-4: 0-33%
** Stage
*** Ta, T1, CIS: 60-90%
*** T2: 43-75%
*** T3: 16-33%
*** T4: 0-5%
*** N+: 0-4%
*** M+: 0%
*'''<span style="color:#ff0000">Prognostic factors</span>'''
**'''<span style="color:#ff0000">Tumour factors</span>'''
**# '''<span style="color:#ff0000">Stage</span>'''
**#* '''<span style="color:#ff0000">Most important prognostic factor</span>'''
**#** '''<span style="color:#ff0000">Non–organ confined disease (>pT2) is the most significant predictor of the development of metastases</span>'''
**# '''<span style="color:#ff0000">Grade</span>'''
**#* '''<span style="color:#ff0000">High-grade tumours are more likely to:</span>'''
**#*# '''<span style="color:#ff0000">Invade</span>''' into the underlying connective tissue, muscle, and surrounding tissues
**#*# '''<span style="color:#ff0000">Be associated with concomitant CIS</span>'''
**#* '''<span style="color:#ff0000">While there is strong correlation between stage and grade, each independently predicts post-operative recurrence</span>'''
**# '''<span style="color:#ff0000">Architecture</span>'''
**#* '''≈85% of renal pelvic tumors are papillary and the remainder sessile'''
**#* '''<span style="color:#ff0000">Papillary tumors seem to have better outcomes than sessile lesions</span>'''
**#** Invasion of the lamina propria or muscle (stage T1 or T2) occurs in 50% of papillary and in >80% of sessile tumors
**#* '''CIS of the upper tract is associated with higher risk for disease progression''' (similar to bladder cancer) and a likelihood of future development of invasive urothelial cancers.
**# '''Size'''
**#* Tumours > 3-4 cm may be associated with worse survival as well as a higher risk of bladder recurrence
**# '''<span style="color:#ff0000">Location</span>'''
**#* '''<span style="color:#ff0000">Renal pelvic tumours are usually more aggressive than ureteral tumours</span>'''
**#** '''<span style="color:#ff0000">50-60% of renal pelvic tumors are invasive''' into either the lamina propria or muscle, </span>'''in''' '''contrast to most bladder tumors, which are usually non-invasive'''
**#** '''<span style="color:#ff0000">55-75% of ureteral tumors are low grade and low stage, but invasion is still more common than bladder tumors</span>'''
**#** The renal parenchyma may be a barrier, slowing distant spread of stage T3 renal pelvis tumors. In contrast, periureteral tumor extension carries a high risk of early tumor dissemination along the periureteral vascular and lymphatic supply. Improved survival of patients with stage T3 renal pelvis tumors versus ureteral tumors has been reported
**#* '''Conflicting results on whether the location of an upper tract tumor affects prognosis'''
**# '''Multifocality'''
**#* Defined as presence of tumor in ≥2 sites within urothelium
**#* Independent predictor of poor clinical outcome
**# '''Tumour necrosis'''
**#* Conflicting evidence on the influence of tumour necrosis on survival
**# '''Lymph node involvement'''
**#* Although lymphadenectomy is seldom performed for clinically node-negative disease, '''pathologic lymph node status is a strong predictor of post-nephroureterectomy recurrence'''
**# LVI
**#* Associated with worse survival in patients without positive nodes; no association in N+ disease
**# Hydronephrosis
**#* Independently associated with advanced disease stage and poor survival
**# Positive surgical margins
**# Previous or concomitant bladder tumours
** '''Patient factors'''
**# Age
**#* Increasing age associated with worse survival
**# Race
**#* Black non-Hispanic race is associated with increased mortality
** '''Surgical factors'''
**# Lack of post-operative mitomycin C instillation
* '''3 particular forms of UTUC,''' 2 associated with environmental exposure ('''aristolochic acid nephropathy''', which includes Balkan and Chinese herbal nephropathy, as well as those seen in arsenic-endemic regions), '''analgesic abuse, and those associated with Lynch syndrome, have an even higher tendency have multiple and bilateral recurrences than do sporadic tumors'''
<h2>Surveillance and Survivorship</h2>
<h2>Surveillance and Survivorship</h2>
===Oncologic Surveillance===
===Oncologic Surveillance===
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