Editing Upper Urinary Tract Urothelial Cancer (section)

== 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>
===Oncologic Surveillance===
*The primary aims of postoperative surveillance for UTUC are to identify 
**Urothelial recurrences
**De novo tumours of the urinary tract
**Regional/distant metastases at early stages when they may be amenable to treatment
* '''Recurrence after'''
**'''Nephron-sparing approaches'''
***'''Most patients following nephron-sparing procedures will develop ipsilateral upper tract recurrences.'''
**** '''Ipsilateral upper tract tumor usually occurs in a proximal-to-distal direction'''; recurrence proximal to the original lesion is rare.
**** '''This high rate of ipsilateral recurrence results in part from a multifocal field change, which is even more pronounced than in bladder cancer'''
**'''Nephroureterectomy'''
*** '''Intravesical recurrence'''
****<span style="color:#ff0000">'''≈30% patients with UTUC will subsequently develop bladder cancer after nephroureterectomy or nephron-sparing procedures'''</span>
***** '''Most recurrences occur within the first 2 years'''
******'''Median time to bladder recurrence 6-12 months'''
******Unclear how long bladder surveillance should continue for after 2 years
***** '''Given the high incidence of metachronous bladder involvement, routine bladder surveillance should be performed in patients with a history of UTUC'''
***** '''Potential explanations on why bladder cancers following UTUC are more common than UTUC following bladder cancer include:'''
*****# '''Downstream seeding'''
*****# '''Longer exposure time to carcinogens in the bladder'''
*****# '''Greater number of urothelial cells in the bladder that are subject to random carcinogenic events'''
****Risk factors for intravesical recurrence:
****#Male sex
****#Previous bladder cancer
****#Preoperative CKD
****#Positive preoperative urinary cytology
****#Ureteral tumor size
****#Multifocality
****#Invasive pathologic T-stage
****# Presence of necrosis
****#Laparoscopic approach
****#Extravesical bladder cuff removal
****# Positive surgical margins
****#Prior ureteroscopic biopsy
****'''Given the substantial risk of local (bladder) recurrences within the first years following nephroureterectomy, risk adapted surveillance with cystoscopy and urine cytology at routine intervals is indicated to facilitate prompt detection of bladder recurrences.'''
***'''Contralateral recurrence'''
**** '''Risk of recurrence to the contralateral upper tract: ≈2%'''
***Locoregional, retroperitoneal, and distant metastases
****Risk factors
*****Multifocality
*****Stage T3-4
*****Grade G3
*****Presence of lymph node metastasis
****Intrabdominal recurrences
*****Very low rates in low-risk patients
******Retroperitoneum or pelvis occurred in ≈5%
*****In patients with HG disease, LVI, or tumor multifocality, periodic imaging of the abdomen and pelvis is warranted, particularly for the first 2 years
****Port-site occur very infrequently, usually associated with inadvertent entry into the collecting system.
****Distant metastases
*****Occurred following nephroureterectomy in 16% of patients.
***** Median time to metastases was 13-16 months.
*****Location of metastases
******Lung metastasis (5%)
*******Low risk in patients with <pT2 N0/M0
*******Can occur in patients with high-grade disease, so periodic chest imaging is warranted
********Chest imaging can be done via chest x-ray or CT
*********Chest x-ray is likely sufficient, less costly, and associated with less radiation exposure
******Bone (4%)
******Liver (4%)
******Brain
*******Rare following nephroureterectomy
*******Patients undergoing follow-up for HR UTUC following nephroureterectomy with acute neurological signs or symptoms should undergo prompt neurologic evaluation with cross-sectional imaging of the brain and/or spine by CT or MRI
******Adrenal gland
******Non-regional lymph nodes
*'''<span style="color:#ff0000">Post-operative evaluation must routinely include evaluation of the:</span>'''
*# '''<span style="color:#ff0000">Bladder, through</span>'''
*#*'''<span style="color:#ff0000">Cystoscopy</span>'''
*# '''<span style="color:#ff0000">Ipsilateral (if organ-sparing therapy was chosen) and contralateral urinary tracts, through</span>'''
*#*'''<span style="color:#ff0000">Upper tract endoscopy</span>'''
*#*'''<span style="color:#ff0000">Upper tract imaging</span>'''
*#**'''<span style="color:#ff0000">Preferred modality: CT urogram</span>'''
*#***'''<span style="color:#ff0000">If patient unable to receive iodinated contrast, use MR urography or retrograde pyelography combined with non-contrast axial imaging</span>'''
*#*'''<span style="color:#ff0000">Urine cytology</span>'''
*# '''<span style="color:#ff0000">Extra-urinary sites for local and metastatic spread, through</span>'''
*#*'''<span style="color:#ff0000">CXR or CT chest</span>'''

==== Schedule ====

===== AUA =====

* '''See [https://www.auanet.org/images/Guidelines/Guideline%20Images/UTUC%202023/Table%206%20UTUC%20Word%20Version.jpg Table] from Original Guidelines'''

====== Surveillance after kidney sparing ======
*'''Low-risk patients managed with kidney sparing treatment'''
**'''Cystoscopy and upper tract endoscopy within 1-3 months of treatment to confirm successful treatment.'''
**If successful treatment confirmed (no evidence of disease), perform
***Cystoscopy of the bladder once again within the first year after treatment, then at least every 6-9 months for the first 2 years and then at least annually thereafter.
**** Upper tract endoscopy at 6 months and 1 year [after treatment].
*****Can be subsequently performed for any symptoms or significant findings on upper tract imaging.
****Upper tract imaging should be performed at least every 6-9 months for first 2 years, then annually up to 5 years.
****Surveillance after 5 years in the absence of recurrence should be based on shared decision-making.
**No distant metastatic evaluation since risk is low with low-risk disease
*'''High-risk patients managed with kidney sparing treatment'''
**'''Cystoscopy, upper tract endoscopy, and upper tract urine cytology within 1-3 months of treatment to confirm successful treatment.'''
**If successful treatment confirmed (no evidence of disease), perform
***Cystoscopy of the bladder and cytology at least every 3-6 months for the first 3 years and then every 6-12 months up to 5 years.
***Upper tract endoscopy should be performed at least at 6 months and 1 year [after treatment]
***Upper tract imaging and BMP should be performed every 3-6 months for 3 years, then every 6-12 months for 2 years, and then annually thereafter.
***Distant metastatic evaluation: Chest imaging (chest X-ray or CT) is recommended every 6-12 months to evaluate for intrathoracic metastasis up to 5 years following last diagnosis/treatment
***Surveillance after 5 years in the absence of recurrence should be based on shared decision-making.
*'''If patient develops urothelial recurrence in the bladder or urethra or positive cytology following kidney sparing treatment for UTUC, evaluate for possible ipsilateral recurrence or development of new contralateral upper tract disease.'''
======Surveillance after radical nephroureterectomy ======
*'''<pT2 N0/M0 managed with NU'''
**Cystoscopy and urine cytology within 3 months after surgery, then repeated based on pathologic grade.
***For LG this should repeated at least every 5-9 months for the first 2 years and then at least annually thereafter.
***For HG, this should be repeated at least every 3-6 months for the first 3 years and then at least annually thereafter.
**Cross-sectional imaging of the abdomen and pelvis should be done within 6 months after surgery and then at least annually for a minimum of 5 years***Due to the metastasis risk and estimated 5% probability for contralateral disease
***Follow up after nephroureterectomy for patients with non-muscle invasive, node-negative UTUC should be largely focused on the risk of intravesical recurrence
** Surveillance after five years in the absence of recurrence should be encouraged and based on shared decision-making between the patient and clinician
*'''T2+ managed with NU'''
**Cystoscopy with cytology at 3 months after surgery, then every 3-6 months for 3 years, and then annually thereafter.
**Cross-sectional imaging of the abdomen and pelvis with multiphasic contrast-enhanced CT urography should be performed every 3-6 months for years 1 and 2, every 6 months at year 3, and annually thereafter to year 5.
**Chest imaging, preferably with chest CT, every 6-12 months for the first 5 years.
**Beyond five years after surgery in patients without recurrence, ongoing surveillance with cystoscopy and upper tract imaging may be continued on an annual basis according to principles of shared/informed decision-making
*'''Sequelae of nephroureterectomy'''
**'''Repeat assessment of blood pressure, eGFR, and proteinuria should be performed soon after nephroureterectomy then again in 3-6 months to assess for development or progression of CKD.'''
***With significant nephron mass loss, hyperfiltration can occur resulting in glomerular damage, exacerbation of proteinuria and progressive sclerosis with further decline in GFR.
*** The long-term impact of renal dysfunction increases risks of osteoporosis, anemia, metabolic and cardiovascular disease, hospitalization and death.
***Effective treatment strategies are available to slow the progression of CKD and reduce cardiovascular risks, and therefore timely identification of progressive renal dysfunction and/or proteinuria can provide opportunity for medical intervention when indicated.
****Careful management of DM and HTN and avoidance of substantial weight gain may slow or prevent CKD progression and should be prioritized on a long-term basis
****Identifying modifiable risk factors including diabetes mellitus (DM), hypertension (HTN) and smoking is essential. Optimizing glycemic and blood pressure control, smoking cessation and minimizing risk of acute kidney injury (with avoidance of hypotension and nephrotoxic agents such as intravenous contrast or non-steroidal anti-inflammatory drugs) should reduce the degree of renal dysfunction in the perioperative period.
***'''In patients who develop progressive renal insufficiency or proteinuria should be referred to nephrology.'''
**Other laboratory evaluations (e.g., CBC, LDH, liver function tests, and alkaline phosphatase) may be obtained at the discretion of the clinician or if advanced disease is suspected.

===== CUA =====

*'''See [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6114151/table/t6-cuaj-8-243/ Table] from [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6114151/ 2018 CUA Surveillance guidelines based on recurrence patterns for upper tract urothelial carcinoma]'''
*'''Bladder'''
** '''Should be assessed with cytology and cystoscopy in all patients at months 3, 6, 12, 18, 24 and annually thereafter for up to 10 years of recurrence-free survival'''
* '''<span style="color:#ff0000">Ipsilateral upper tract</span>'''
** '''<span style="color:#ff0000">Should be assessed by URS and selective cytology or biopsy in all patients following nephron-sparing procedures at months 3, 6, 12, 18, 24 and annually thereafter up to 10 years of recurrence-free survival</span>'''
*** '''<span style="color:#ff0000">Computed tomography urography (CTU) and retrograde pyelography lacks sensitivity</span>'''
* '''Extra-urinary sites'''
** '''<span style="color:#ff0000">Routine blood work should include:</span>'''
*** '''<span style="color:#ff0000">Renal function tests</span>'''
*** '''<span style="color:#ff0000">Metabolic panel, including liver function tests, calcium and alkaline phosphatase</span>'''
** '''<span style="color:#ff0000">To assess for local, contralateral and distant metastases</span>''' in patients after nephroureterectomy or nephron-sparing procedures, '''<span style="color:#ff0000">imaging of the abdomen and pelvis with CTU is recommended</span>'''
*** MRI or US may be substituted for CTU in patients with contraindications to CTU
*** '''CXR is recommended to assess for lung metastases'''
*** Bone scan is indicated in the presence of bone pain, elevated calcium or elevated alkaline phosphatase to assess for bone metastases
* '''Lack of evidence for an optimal duration of surveillance; recommended approach:'''
** '''High-grade, pT≥2 or pN+: lifelong annual surveillance with history, physical examination, blood work, urine cytology and abdominal/chest imaging'''
** '''Low-grade, pT<2 pN0/x: annual cystoscopy and ipsilateral ureteroscopy (following nephron-sparing procedures) may be omitted after 10 years of recurrence-free survival; after 10 years of recurrence-free survival, patients with may be discharged from annual surveillance'''

===Survivorship===
*Discuss disease-related stresses and risk factors and encourage patients with urothelial cancer to adopt healthy lifestyle habits, including smoking cessation, exercise, and a healthy diet, to promote long-term health benefits and quality of life.
**UTUC is associated with metabolic syndrome and obesity, with obesity adversely impacting disease-specific outcomes among patients undergoing RNU.
**Clinicians should work with patients and their primary care providers to ensure that comorbidities are optimally managed throughout the course of care for UTUC and during surveillance to maximize quality of life during survivorship.
<h2>Questions</h2>
  <ol>
   <li>What are the risk factors for upper tract urothelial carcinoma (UTUC)?</li>
   <li>Which other malignancies are associated with Lynch syndrome?</li>
   <li>In patients with bladder cancer, what is the risk of subsequent UTUC? In patients with UTUC, what is the risk of subsequent bladder cancer?</li>
   <li>in patients that have undergone cystectomy for bladder cancer, which of the following is not a risk factor for subsequent UTUC?</li>
   <li>What is the most important predictor of developing metastasis?</li>
   <li>What is the differential diagnosis of a filling defect in the collecting system?</li>
   <li>What is the most important prognostic factor for survival in UTUC?</li>
   <li>What are the indications for nephroureterectomy? Segmental ureterectomy?</li>
  </ol>
	<h2>Answers</h2>
  <ol>
   <li>What are the risk factors for upper tract urothelial carcinoma (UTUC)?</li>
   <ol>
    <li>Smoking</li>
    <li>Occupational exposure</li>
    <li>Chronic inflammation</li>
    <li>Cyclophosphamide exposure</li>
    <li>Analgesic abuse</li>
    <li>Lynch syndrome</li>
    <li>Exposure to aristolocholic acid (Balkan nephropathy)</li>
    <li>Exposure to arsenic</li>
   </ol>
   <li>Which other malignancies are associated with Lynch syndrome?
    <ul>
     <li>Colonic (most common), endometrial (second most common), prostate, urothelial, adrenal, gastric, pancreatic, uterine, ovarian, and sebaceous carcinomas </li>
    </ul>
   </li>
   <li>In patients with bladder cancer, what is the risk of subsequent UTUC? In patients with UTUC, what is the risk of subsequent bladder cancer?
    <ul>
     <li>2-4% patients with bladder cancer will subsequently develop UTUC,</li>
     <li>≈30% patients with UTUC will subsequently develop bladder cancer after nephroureterectomy or nephron-sparing procedures</li>
    </ul>
   </li>
   <li>In patients that have undergone cystectomy for bladder cancer, which of the following is not a risk factor for subsequent UTUC?</li>
   <ol>
    <li>Presence of CIS</li>
    <li>N0 status</li>
    <li><u>High-grade tumours</u></li>
    <li>Involvement of male prostatic urethra or female urethra</li>
   </ol>
   <li>What is the most important predictor of developing metastasis?
    <ul>
     <li>T stage &gt; 2</li>
    </ul>
   </li>
   <li>What is the differential diagnosis of a filling defect in the collecting system?</li>
   <ol>
    <li>Tumour</li>
    <li>Blood clot</li>
    <li>Stone</li>
    <li>Sloughed papilla</li>
    <li>Fungus ball</li>
    <li>Overlying bowel gas</li>
    <li>External compression</li>
   </ol>
   <li>What is the most important prognostic factor for survival in UTUC?
    <ul>
     <li>Stage; recall in bladder grade has stronger association with progression of NMIBC than stage</li>
    </ul>
   </li>
   <li>What are the indications for nephroureterectomy? Segmental ureterectomy?
    <ul>
     <li>Nephroureterectomy: high-grade or pT2</li>
     <li>Segmental ureterectomy: 
      <ul>
       <li>Low-grade, low-stage tumors that are not able to be removed endoscopically because of tumor size or multiplicity </li>
       <li>High-grade or invasive tumors when preservation of renal unit is necessary </li>
      </ul>
     </li>
    </ul>
   </li>
   </ol><h2>References</h2>
   <ul>
    <li>Wein AJ, Kavoussi LR, Partin AW, Peters CA (eds): CAMPBELL-WALSH UROLOGY, ed 11. Philadelphia, Elsevier, 2015, vol 1, chap 58</li><li>[https://pubmed.ncbi.nlm.nih.gov/37096584/ Coleman, Jonathan A., et al. "Diagnosis and Management of Non-Metastatic Upper Tract Urothelial Carcinoma: AUA/SUO Guideline." ''The Journal of Urology'' 209.6 (2023): 1071-1081.]
</li>
   </ul>