Editing Upper Urinary Tract Urothelial Cancer

<h5><strong><a name="epidemiology">Epidemiology</a></strong><a href="https://seer.cancer.gov/">§</a></h5>
	<ul>
		<li>Incidence
<ul>
	      <li>Relatively rare	        
	        <ul>
	          <li>US incidence: 2/100,000
	            <ul>
	              <li><strong><span class="red">Tumors  of the renal pelvis are slightly more common than ureteral tumors</span></strong><span class="red"><a href="https://seer.cancer.gov/">§</a></span>
	                <ul>
	                  <li>Renal pelvis: 1.2/100,000</li>
	                  <li>Ureter: 0.8/100,000
	                    <ul>
	                      <li><strong><span class="red">Ureteral  tumours occur more commonly in the lower ureter (70%) </span></strong><strong>than  in the upper ureter (25% mid, 5% upper). This may be a reflection of downstream  implantation. </strong></li>
                        </ul>
	                  </li>
                    </ul>
                  </li>
                </ul>
              </li>
            </ul>
	      </li>
	      <li>Higher incidence   in Balkan countries</li>
</ul>
		</li>
		<li>Age
		  <ul>
		    <li>Peak incidence  age 70s and 80s <strong>(older than bladder cancer patients)</strong>
		      <ul>
		        <li><strong>Presentation at age &lt;60 should raise  concern of hereditary UTUC as part of Lynch syndrome</strong></li>
	          </ul>
		    </li>
	      </ul>
	    </li>
		<li><strong>Gender</strong>
		  <ul>
		    <li><strong>M:F 2:1 (unlike  bladder which is M:F 4:1)</strong></li>
	      </ul>
		</li>
		<li>Race
		  <ul>
		    <li>Caucasians are  2x more likely as African-Americans to develop UTUC</li>
	      </ul>
	    </li>
	</ul>
	<h5><strong><span class="red">Pathogenesis</span></strong></h5>
    <ul>
	  <li><strong><span class="red"><a name="riskfactors">Risk factors</a></span></strong>
        <ul>
          <li><strong><span class="red">Hereditary</span></strong>
            <ul>
              <li><strong><span class="red">Lynch syndrome (hereditary nonpolyposis colorectal carcinoma (HNPCC))</span></strong>
                <ul>
                  <li><strong><span class="red">Mutation:  DNA mismatch repair genes </span></strong>(MLH1,  MSH2, MSH6, and PMS2)</li>
                  <li><strong><span class="red">May  develop (8) colonic (most common), endometrial (second most common), prostate,  urothelial, adrenal, </span></strong><strong>gastric,  pancreatic, uterine, ovarian, and sebaceous carcinomas</strong></li>
                  <li><strong>The urothelial  cancers mainly arise in the upper tract, and it is unclear if carriers of these  mutations may also have a higher risk of bladder malignancy</strong></li>
                  <li>Unlike  with non-hereditary cancers, patients are younger (mean age 55 years) and are  more likely to be female</li>
                </ul>
              </li>
            </ul>
          </li>
          <li><strong><span class="red">External  (7)</span></strong>
            <ul>
              <li><strong><span class="red">Risk factors shared with bladder cancer (5)</span></strong>
                <ol>
                  <li><strong><span class="red">Smoking</span></strong>
                    <ul>
                      <li><strong><span class="red">Cigarette  smoking is the most important modifiable risk factor for UTUC</span></strong></li>
                      <li>Smoking  cessation decreases subsequent risk</li>
                    </ul>
                  </li>
                  <li><strong><span class="red">Occupational exposure</span></strong>              
                    <ul>
                      <li><strong>Exposure to  aromatic hydrocarbons</strong>, especially  those used in the chemical, petrol, and plastic industries; other occupations  at risk are those with exposure to coal, asphalt, or tar</li>
                    </ul>
                  </li>
                  <li><strong><span class="red">Chronic inflammation, infection, or iatrogenesis</span></strong>
                    <ul>
                      <li>Chronic  bacterial infection associated with urinary stones and obstruction has been  associated with the development of squamous cell cancer (and less commonly  adenocarcinoma)</li>
                    </ul>
                  </li>
                  <li><strong><span class="red">Alkylating chemotherapy</span></strong>              
                    <ul>
                      <li><strong>Cyclophosphamide</strong> or ifosfamide</li>
                    </ul>
                  </li>
                  <li><strong><span class="red">Analgesic abuse</span></strong><strong> </strong>
                    <ul>
                      <li>Phenacetin is  the most well described causative agent in analgesic nephropathy, others  include codeine, acetaminophen, and aspirin.</li>
                      <li>The number of cases  attributed to phenacetin has decreased since phenacetin was replaced by its non-toxigenic  metabolite acetaminophen</li>
                    </ul>
                  </li>
                </ol>
              </li>
              <li><strong><span class="red">Unique to UTUC (2):</span></strong>
                <ol>
                  <li><strong><span class="red">Aristolochic acid </span></strong>              
                    <ul>
                      <li>Found in plants (Aristolochia  fangchi and Aristolochia clematitis) and has mutagenic action; the associated  mutation is predominant in patients with Balkan endemic nephropathy and Chinese  herb nephropathy. These plants are endemic in Balkan countries and grow as  weeds in wheat fields. The incidence of Balkan endemic nephropathy is  decreasing.</li>
                    </ul>
                  </li>
                  <li><strong><span class="red">Arsenic</span></strong>
                    <ul>
                      <li>Exposure can be  from drinking water from artesian wells</li>
                    </ul>
                  </li>
                </ol>
              </li>
            </ul>
          </li>
        </ul>
      </li>
    </ul>
	<h5><strong><span class="red"><a name="pathology">Pathology</a></span></strong></h5>
    <ul>
      <li><strong>Normal upper  tract urothelium</strong></li>
      <ul>
        <li><strong>Bladder is  derived from the endoderm; ureter and renal pelvis are derived from the  mesoderm</strong></li>
        <li>The urothelial  lining of the upper urinary tract closely approximates that of the bladder  except for the markedly reduced thickness of the muscle layer and the abutting  of the urothelium to the renal parenchyma proximally. </li>
        <li>The epithelial  layer is continuous from the level of the calyces to the distal ureter. 
          <ul>
            <li>It has  been postulated that the urothelial layer may even &ldquo;extend&rdquo; into the collecting  ducts, raising the possibility that collecting duct renal cancers may be  closely related to urothelial cancers and perhaps better treated by agents used  for urothelial cancers</li>
          </ul>
        </li>
        <li><strong>Renal  pelvis and calyces</strong></li>
        <ul>
          <li><strong>The  walls of the calyces and the pelvis</strong> <strong>contain</strong> fibrous connective tissue and 2 layers of <strong>smooth muscle</strong> and are lined on their inner surfaces with urothelium</li>
        </ul>
        <li>Ureter</li>
        <ul>
          <li>The  3 muscular layers of the ureter merge with the 3 muscular layers of the bladder      </li>
        </ul>
      </ul>
      <li><strong><span class="red">Abnormal  urothelium</span></strong></li>
      <ul>
        <li><strong><span class="red">Benign lesions</span></strong></li>
        <ul>
          <li><strong>Papillomas and  inverted papillomas </strong>
            <ul>
              <li><strong>Generally considered benign lesions</strong></li>
              <li><strong>Association with either synchronous or metachronous UTUC</strong>
                <ul>
                  <li><strong>Follow-up  for all cases of inverted papilloma should be continued for at least 2 years  after initial diagnosis</strong></li>
                </ul>
              </li>
            </ul>
          </li>
          <li><strong>Von Brunn Nests </strong>
            <ul>
              <li><strong>Reactive proliferation, considered a variation of normal urothelium.</strong></li>
            </ul>
          </li>
        </ul>
        <li><strong><span class="red">Metaplasia and dysplasia</span></strong></li>
        <ul>
          <li><strong><span class="red">In a significant proportion of patients, UTUCs progress from  hyperplasia to dysplasia to frank CIS</span></strong></li>
        </ul>
        <li><strong><span class="red">Urothelial carcinoma</span></strong></li>
        <ul>
          <li><strong><span class="red">Majority  (90%) of upper tract tumours are urothelial carcinoma</span></strong><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5308053/">§</a>
            <ul>
              <li>Squamous and adenocarcinomas  comprise a small minority. </li>
            </ul>
          </li>
          <li><strong>UTUC  are histologically similar to urothelial carcinoma of the bladder, but <span class="red">the relative thinness of the muscle layer of the renal pelvis  and ureter may allow earlier penetration of invasive upper tract tumors than is  seen in bladder neoplasms. </span></strong>
            <ul>
              <li><strong><span class="red">UTUC  is more often invasive and poorly differentiated than bladder cancers. However,  in pathologically matched cohorts, cancer-specific outcomes are comparable  between urothelial tumours of the upper tract and bladder</span></strong></li>
            </ul>
          </li>
          <li><strong>Reported  variants of urothelial carcinoma are squamous cell, glandular, sarcomatoid,  micropapillary, neuroendocrine, and lymphoepithelial</strong>. <strong></strong></li>
          <ul>
            <li>Although all of  these variants are considered aggressive tumors, after adjustment for the rest of  clinicopathologic characteristics, <strong><span class="red">variant histology  has not been shown to predict poor clinical outcome in UTUC (unlike bladder cancer)</span></strong></li>
          </ul>
        </ul>
        <li><strong><span class="red">Non-urothelial carcinoma</span></strong></li>
        <ul>
          <li><strong><span class="red">Most commonly squamous cell carcinoma and adenocarcinoma</span></strong></li>
          <ul>
            <li><strong>Squamous</strong></li>
            <ul>
              <li><strong>Frequently  associated with a condition of chronic inflammation or infection or with  analgesic abuse</strong></li>
              <li><strong>Typically more  aggressive at presentation</strong></li>
              <li>Occur  6x more frequently in the renal pelvis than in the ureter </li>
            </ul>
            <li><strong>Adenocarcinoma</strong></li>
            <ul>
              <li>Rare</li>
              <li><strong>Typically  associated with long-term obstruction</strong>,  <strong>inflammation, or urinary calculi </strong></li>
            </ul>
          </ul>
        </ul>
      </ul>
    </ul>
	<h5><strong><span class="red"><a name="tnm">TNM staging</a></span> (AJCC 8th edition<a href="https://cancerstaging.org/references-tools/deskreferences/Documents/AJCC%20Cancer%20Staging%20Form%20Supplement.pdf">§</a>)</strong></h5>
    <ul>
      <li><strong><span class="red">Tstage</span></strong></li>
      <ul>
        <li><strong>TX: tumour  cannot be assessed</strong></li>
        <li><strong>T0: no evidence  of tumour</strong></li>
        <li><strong><span class="red">Ta:  non-invasive (confined to epithelial mucosa) papillary carcinoma</span></strong></li>
        <li><strong><span class="red">Tis:  carcinoma in-situ</span></strong></li>
        <li><strong><span class="red">T1: invades lamina propria </span></strong>(subepithelial connective tissue)</li>
        <li><strong><span class="red">T2:  invades muscle</span></strong></li>
        <li><strong><span class="red">T3</span></strong></li>
        <ul>
          <li><strong><span class="red">Renal  pelvis: tumour invades beyond muscularis into peripelvic fat or renal  parenchyma</span></strong></li>
          <li><strong><span class="red">Ureter:  tumour invades beyond muscularis into periureteric fat</span></strong></li>
        </ul>
        <li><strong><span class="red">T4: invades  adjacent organs or through the kidney into perinephric fat</span></strong></li>
      </ul>
      <li>Nstage
        <ul>
          <li>NX: regional lymph nodes cannot be assessed </li>
          <li>N0: no regional lymph node metastasis </li>
          <li>N1: metastasis ≤2 cm in greatest dimension, in a single lymph node </li>
          <li>N2: metastasis &gt;2 cm in a single lymph node; or multiple lymph nodes </li>
        </ul>
      </li>
      <li>Mstage </li>
      <ul>
        <li>MX: distant metastasis cannot be assessed </li>
        <li>M0: no distant metastasis </li>
        <li>M1: distant metastasis </li>
      </ul>
    </ul>
	<h5><strong><span class="red"><a name="naturalhistory">Natural history</a></span></strong></h5>
    <ul>
      <li><strong>Most occurrences  are in a single renal unit</strong></li>
      <ul>
        <li><strong>Synchronous  bilateral UTUC</strong>
          <ul>
            <li><strong>Rare (&lt;2%)</strong></li>
            <li>Risk  of bilateral disease and multifocality increases with the presence of CIS</li>
          </ul>
        </li>
        <li>Metachronous  UTUC occurrences are 80% after bladder cancer and 2-6%  after contralateral UTUC      </li>
      </ul>
      <li><strong><span class="red">2-4% patients with bladder cancer will subsequently develop UTUC</span></strong>
        <ul>
          <li>Interval ranges from 17-170 months</li>
          <li><strong>Risk factors for subsequent UTUC in patients undergoing cystectomy for bladder cancer</strong>
            <ul>
              <li><strong>Low-grade tumors</strong></li>
              <li><strong>Non–muscle invasive tumors</strong></li>
              <li><strong>N0 status</strong></li>
              <li><strong>Presence of CIS</strong></li>
              <li><strong>Multiple urothelial recurrences</strong></li>
              <li><strong>Multifocal tumors</strong></li>
              <li><strong>History of previous UTUC</strong></li>
              <li><strong>Positive ureteral margin</strong></li>
              <li><strong>Involvement of male prostatic urethra or female  urethra</strong>
                <ul>
                  <li>Based on meta-analysis of 27 studies with 13,185 patients (<a href="https://www.ncbi.nlm.nih.gov/pubmed/23083867">Picozzi et al, 2012</a>) </li>
                </ul>
              </li>
            </ul>
          </li>
          <li>Long-term surveillance of the upper tract  is important in  bladder cancer  patients</li>
        </ul>
      </li>
      <li><strong><span class="red">≈30% patients with UTUC will subsequently develop bladder cancer after  nephroureterectomy or nephron-sparing procedures</span></strong></li>
      <ul>
        <li>Median time to bladder  recurrence 6-12 months</li>
        <li><strong>Given the high  incidence of metachronous bladder involvement,  routine bladder  surveillance should be performed in patients with a history of UTUC</strong></li>
        <li>Potential  explanations on why bladder cancers following UTUC are more  common than UTUC following bladder cancer include: 
          <ol>
            <li>Downstream  seeding</li>
            <li>Longer exposure time to carcinogens in the bladder</li>
            <li>Greater number  of urothelial cells in the bladder that are subject to random carcinogenic  events</li>
          </ol>
        </li>
      </ul>
      <li><strong>UTUC may spread </strong>in  the same ways as bladder tumors do via<strong> direct invasion into the renal  parenchyma or surrounding structures, lymphatic or hematogenous invasion, and  epithelial spread by seeding or direct extension.</strong></li>
      <ul>
        <li><strong><span class="red">Lymphatic</span></strong>: </li>
        <ul>
          <li><strong><span class="red">Lymphatic spread  from the upper urinary tract depends on the location of the tumor:</span></strong></li>
          <ul>
            <li><strong><span class="red">Renal pelvis and  upper ureteral tumors spread initially from hilar to para-aortic and paracaval  nodes</span></strong></li>
		    <li><strong><span class="red">Distal ureteral  tumors spread to pelvic nodes</span></strong></li>
          </ul>
          <li><strong>Risk of  lymphatic spread is directly related to the depth of invasion (stage) of the  primary tumor</strong></li>
        </ul>
        <li><strong>Hematogenous: </strong></li>
        <ul>
          <li><strong>Most  common sites of hematogenous metastases: liver, lung, and bone</strong></li>
        </ul>
        <li><strong>Epithelial: </strong></li>
        <ul>
          <li><strong>Epithelial  spreading may occur in both antegrade and retrograde manners.</strong></li>
          <ul>
            <li>Antegrade  seeding is more common and thought to be the most likely explanation for the  high incidence of recurrence in patients in whom a ureteral stump is left in  situ after nephrectomy and incomplete ureterectomy</li>
          </ul>
        </ul>
      </ul>
      <li><strong>Panurothelial  disease</strong></li>
      <ul>
        <li><strong>Defined as a  disease involving the bladder and 2 extravesical sites</strong></li>
        <ul>
          <li>In  males, this could include one or both upper urinary tracts and/or the prostatic  urethra</li>
          <li>In  females, this could be the bladder and both upper urinary tracts. </li>
        </ul>
        <li>The low incidence  and the lack of prospective studies do not permit absolute conclusions about  treatment impact and outcomes    </li>
      </ul>
    </ul>
	<h5><strong><span class="red"><a name="diagnosis">Diagnosis and Evaluation of UTUC</a></span></strong></h5>
    <ul>
      <li><strong><span class="red">UrologySchool.com Summary</span></strong>
        <ul>
          <li><strong><span class="red">H+P</span></strong></li>
          <li><strong><span class="red">Labs: cytology, LFTs</span></strong></li>
          <li><strong><span class="red">Imaging: </span></strong>
            <ul>
              <li><strong><span class="red">Primary: CT urography, retrograde imaging</span></strong></li>
              <li><strong><span class="red">Metastasis: CXR</span></strong></li>
            </ul>
          </li>
          <li><strong><span class="red">Other: </span></strong>
            <ul>
              <li><strong><span class="red">Cystoscopy</span></strong></li>
              <li><strong><span class="red"> URS +/- biopsy</span></strong></li>
              <li><strong><span class="red">Renal mass biopsy</span></strong></li>
            </ul>
          </li>
        </ul>
      </li>
      </ul>
    <p>&nbsp;</p>
    <ul>
      <li><strong><span class="red">History and  physical exam</span></strong></li>
      <ul>
        <li><strong>Most  common presenting sign is hematuria</strong></li>
        <li><strong>Flank pain is  the second most common symptom</strong>. 
          <ul>
            <li>This  pain is typically dull and believed to be <strong>secondary to a gradual onset of  obstruction and hydronephrotic distention</strong>. In some patients, pain can be  acute and can mimic renal colic, typically due to the passage of clots that acutely  obstruct the collecting system.</li>
          </ul>
        </li>
        <li>Some patients  are asymptomatic at presentation and are diagnosed when an incidental lesion is  found on imaging</li>
      </ul>
      <li><strong><span class="red">Laboratory</span></strong>
        <ul>
          <li><strong><span class="red">Cytology and other markers</span></strong></li>
          <ul>
            <li><strong>The sensitivity  of cytology is directly related to tumor grade</strong></li>
            <li><strong>In a patient  with an upper tract filling defect and an abnormal voided cytology,  must be  cautious in determining the site of origin of the malignant cells</strong>.  Ureteral catheterization for collection of urine or washings may provide more  accurate cytologic results. </li>
            <li><strong><span class="red">Causes of false-positive cytology (2):</span></strong>
              <ol>
                <li><strong><span class="red">Contrast agents</span></strong>                </li>
                <ul>
                  <li>Exposure  of urothelial cells to ionic, high-osmolar contrast agents as in retrograde  pyelography may worsen cytologic abnormalities. Thus, cytologic specimens  should be obtained before the use of these agents</li>
                </ul>
                <li><strong>Inflammation from infection or stones</strong> </li>
              </ol>
            </li>
          </ul>
          
          <li><strong>Liver function  tests</strong>
            <ul>
              <li>Liver is a common site of metastasis</li>
            </ul>
          </li>
        </ul>
      </li>
      <li><strong><span class="red">Imaging</span></strong>
        <ul>
          <li><strong><span class="red">Primary</span></strong>
            <ul>
              <li><strong><span class="red">Options:</span></strong>
                <ol>
                  <li><strong>Retrograde ureterogram and pyelogram</strong></li>
                  <li><strong><span class="red">CT  urography</span></strong> 
                  </li>
                </ol>
                <ul>
                  <ul>
                    <li>High sensitivity (100%) and moderate specificity (60%) for upper tract  malignant disease</li>
                  </ul>
                </ul>
              </li>
            </ul>
          </li>
        </ul>
      </li>
    </ul>
    <p>&nbsp;</p>
    <p align="center"><a title="Kristie Guite, Louis Hinshaw and Fred Lee / CC BY (https://creativecommons.org/licenses/by/3.0)" href="https://commons.wikimedia.org/wiki/File:Renal_parenchymal_phase_CT_of_transitional_cell_carcinoma.jpg"><img width="80%" alt="Renal parenchymal phase CT of transitional cell carcinoma" src="https://upload.wikimedia.org/wikipedia/commons/thumb/2/27/Renal_parenchymal_phase_CT_of_transitional_cell_carcinoma.jpg/512px-Renal_parenchymal_phase_CT_of_transitional_cell_carcinoma.jpg"></a></p>
    <p align="center">CT urogram demonstrating filling defect in left renal pelvis</p>
    <p align="center">Source: <a href="https://commons.wikimedia.org/wiki/File:Renal_parenchymal_phase_CT_of_transitional_cell_carcinoma.jpg">Wikipedia</a></p>
    <p align="center">&nbsp;</p>
    <ul>
    <ul>
      <ul>
          <li><strong>Typical findings  suggestive of an upper urinary tract tumor:</strong>
            <ul>
              <li><strong>Radiolucent  filling defects</strong></li>
              <li><strong>Non-visualization  of the collecting system</strong></li>
              <li><strong>Obstruction </strong></li>
            </ul>
          </li>
          <li><strong><span class="red">The  differential diagnosis of a radiolucent filling defect includes (7):</span></strong>
            <ol>
              <li><strong><span class="red">Tumour</span></strong></li>
              <li><strong><span class="red">Blood  clot</span></strong></li>
              <li><strong><span class="red">Stones</span></strong>;  higher HFU than urothelial carcinoma<strong> </strong></li>
              <li><strong><span class="red">Sloughed  papilla</span></strong></li>
              <li><strong><span class="red">Fungus  ball</span></strong></li>
              <li><strong><span class="red">Overlying  bowel gas</span></strong></li>
              <li><strong><span class="red">External compression</span></strong><strong> </strong></li>
            </ol>
          </li>
          <li><strong>Radiolucent,  noncalcified lesions may require additional evaluation by retrograde urography  or ureteroscopy, with or without biopsy and cytology</strong></li>
          <li><strong>Evaluation of  the contralateral kidney is important not only because of possible bilateral  disease but also because it allows a determination of the functionality of the  contralateral kidney</strong></li>
        </ul>
        <li><strong><span class="red">Metastasis</span></strong>
          <ul>
            <li><strong>CXR</strong></li>
            <li><strong>Bone scan, </strong>consider in  the presence of bone pain, elevated calcium or elevated alkaline phosphatase</li>
          </ul>
        </li>
      </ul>
      <li><strong><span class="red">Other</span></strong>
        <ul>
          <li><strong><span class="red">Cystoscopy</span></strong>
            <ul>
              <li><strong><span class="red">Because  upper urinary tract tumors are often associated with bladder cancers,  cystoscopy is mandatory in the evaluation to exclude coexistent bladder lesions</span></strong>          </li>
            </ul>
          </li>
          <li>
            <p><strong><span class="red">URS with biopsy</span></strong></p>
            <ul>
              <li><strong>Diagnostic  accuracy improves with the addition of URS to retrograde imaging</strong></li>
            </ul>
          </li>
        </ul>
      </li>
    </ul>
    <p>&nbsp;</p>
   <p align="center"><a title="Old wombat / CC BY-SA (https://creativecommons.org/licenses/by-sa/4.0)" href="https://commons.wikimedia.org/wiki/File:Cystoscopy_-_Uretereal_Cancer.jpg"><img width="40%" alt="Cystoscopy - Uretereal Cancer" src="https://upload.wikimedia.org/wikipedia/commons/a/af/Cystoscopy_-_Uretereal_Cancer.jpg"></a></p>
    <p align="center">Ureteral tumour on endoscopy</p>
    <p align="center">Source: <a href="https://commons.wikimedia.org/wiki/File:Cystoscopy_-_Uretereal_Cancer.jpg">Wikipedia</a></p>
    <p align="center">&nbsp;</p>
    <ul>
      <ul>
        <ul>
          <li><strong>URS allows  direct visualization of the tumor and biopsy of suspected areas</strong>
            <ul>
              <li>The urologist&rsquo;s  impression of the tumor grade based on ureteroscopic appearance is likely to be  correct in only 70% of cases, suggesting that biopsy is also needed to further  define this important aspect of staging</li>
              
              <li><strong><span class="purple">Systematic review and meta-analysis evaluating diagnostic accuracy of URS biopsy (2020)</span></strong>
                <ul>
                  <li>Included studies comparing URS biopsy to pathology on surgical specimen (radical nephroureterectomy or segmental ureterectomy)</li>
                  <li>Results:
                    <ul>
                      <li>Included 23 studies comprising 2232 patients</li>
                      <li>Moderate to high risk of bias accross studies</li>
                      <li>Stage-to-stage match  
                        <ul>
                          <li>Positive predictive value for cT1+/muscle-invasive: 94%</li>
                          <li>Negative  predictive value  for cTa-Tis/non-muscle-invasive disease of 60% </li>
                        </ul>
                      </li>
                      <li>Grade-to-grade match 
                        <ul>
                          <li>High-grade (cHG/pHG): 97%  </li>
                          <li>Low-grade (cLG/pLG): 66% </li>
                        </ul>
                      </li>
                      <li>Grade-to-stage match
                        <ul>
                          <li>Positive predictive value for cHG/muscle-invasive disease: 60% </li>
                          <li>Negative  predictive value for cLG/non-muscle-invasive disease: 77%</li>
                        </ul>
                      </li>
						<li><strong><span class="red">Overall</span>
                        </strong>
                        <ul>
                          <li>                            <strong><span class="red">32% undergrading</span>                            </strong></li>
                          <li><strong><span class="red">46% understaging</span></strong>
  <ul>
    <li><strong><span class="red">A precise correlation with eventual tumor stage is  difficult </span></strong> mainly because of technical limitations of use of small biopsy instruments  through the narrow channel of the flexible ureteroscope, resulting in  the small size and shallow depth of ureteroscopic biopsy specimens. Brush biopsy may be  used if cup biopsy forceps fail to obtain adequate tissue.</li>
    </ul>
                          </li>
                          </ul>
					  </li>
					</ul>
                  </li>
                  <li><a href="https://pubmed.ncbi.nlm.nih.gov/32674841/">Subiela, José Daniel, et al.</a>"Diagnostic accuracy of ureteroscopic biopsy in predicting stage and grade at final pathology in upper tract urothelial carcinoma: Systematic review and meta-analysis." <em>European Journal of Surgical Oncology</em> (2020).</li>
                </ul>
              </li>
              <li><strong><span class="red">Reasonable histologic correlation</span></strong> (78-92%)</li>
              <li><strong>In  general, CIS of the upper tract is a presumptive diagnosis that is made by the  presence of unequivocally positive selective cytology in the absence of any  radiographic or endoscopic findings</strong></li>
              <li><strong>Is  URS (with or without biopsy) necessary in all cases of suspected upper tract  tumors? No.</strong> In fact, URS should probably be  reserved for situations in which the diagnosis remains in question after  conventional radiographic studies and for those patients in whom the treatment  plan may be modified on the basis of the ureteroscopic findings, for example,  endoscopic resection.</li>
              <li><strong>Technique: Endoscopic  Evaluation and Collection of Urine Cytology Specimen</strong>
                <ul>
                  <li>Summary of Steps
                    <ul>
                      <li>Cystoscopy  is performed and the bladder inspected for concomitant bladder disease. </li>
                      <li>The  ureteral orifice is identified and inspected for lateralizing hematuria. </li>
                      <li>A  small-diameter (6.9 or 7.5 Fr) ureteroscope is passed directly into the ureteral  orifice, and the distal ureter is inspected before any trauma from a previously  placed guidewire or dilation. </li>
                      <li>A guidewire is then placed through the  ureteroscope and up the ureter to the level of the renal pelvis under  fluoroscopic guidance. </li>
                      <li>The flexible ureteroscope is used to visualize the  remaining urothelium. </li>
                      <li>When a lesion or suspicious area is seen, a normal saline  washing of the area is performed before biopsy or intervention. If the ureter  does not accept the smaller ureteroscope, active dilation of the ureter is necessary.</li>
                      <li>Special  circumstances include prior urinary diversion and tumor confined to the  intramural ureter. With cases of prior urinary diversion, identification of the  ureteroenteric anastomosis is difficult and may require antegrade percutaneous  passage of a guidewire down the ureter before endoscopy. The wire can be  retrieved from the diversion, and the ureteroscope can be passed in a  retrograde fashion. The nephrostomy tract does not need to be fully dilated in  this setting</li>
                    </ul>
                  </li>
                </ul>
              </li>
            </ul>
          </li>
        </ul>
        <li><strong>Antegrade  endoscopy</strong>
          <ul>
            <li><strong>Percutaneous  access to the renal pelvis may be required for diagnosis or treatment.</strong> In such cases, antegrade urography and ureteroscopy may be useful for tumor  resection, biopsy, or simple visualization.</li>
          </ul>
        </li>
        <ul>
          <ul>
            <ul>
              <li><strong>Tumor cell  implantation in the retroperitoneum and along the nephrostomy tube tract has  been reported after these procedures</strong>        </li>
            </ul>
          </ul>
        </ul>

        <li>
            <p><strong><span class="red">Renal mass biopsy</span></strong>
            </p>
            <ul>
              <li><strong>Systematic review of 288 patients undergoing percutaneous nephroscopic resection of tumour found a tract seeding rate of 0.3%<a href="https://pubmed.ncbi.nlm.nih.gov/22471401/">§</a></strong>      </li>
            </ul>
        </li>
      </ul>
      <li><strong>Preoperative  determination of the stage of UTUC tumors remains difficult. </strong><strong><span class="red">Therefore, in predicting the tumor stage, a combination of  the radiographic studies, the visualized appearance of the tumor, and the tumor  grade provides the surgeon with the best estimation for risk stratification.</span></strong></li>
    </ul>
	<h5><strong><span class="red"><a name="prognosis">Prognosis</a></span></strong>    </h5>
    <ul>
      <li><strong><span class="red">Tumour factors</span></strong>
        <ul>
          <li><strong><span class="red">Stage</span></strong>
            <ul>
              <li><strong><span class="red">Most  important prognostic factor </span></strong>
                <ul>
                  <li><strong><span class="red">Non–organ  confined disease (&gt;pT2) is the most significant predictor of the development  of metastases</span></strong></li>
                </ul>
              </li>
            </ul>
          </li>
          <li><strong><span class="red">Grade</span></strong>
            <ul>
              <li><strong><span class="red">High-grade  tumours are more likely to:</span></strong>
                <ol>
                  <li><strong><span class="red">Invade </span></strong>into the  underlying connective tissue, muscle, and surrounding tissues</li>
                  <li><strong><span class="red">Be associated with concomitant CIS</span></strong></li>
                </ol>
              </li>
              <li><strong><span class="red">While  there is  strong correlation between stage and grade, each independently  predicts post-operative recurrence</span></strong></li>
            </ul>
          </li>
			<li><strong><span class="red">Architecture</span></strong>
              <ul>
              <li><strong>≈85% of renal  pelvic tumors are papillary and the remainder sessile</strong></li>
              <li><strong><span class="red">Papillary tumors  seem to have better outcomes than sessile lesions</span></strong>
                <ul>
                  <li>Invasion of the lamina propria or muscle (stage T1 or T2) occurs in 50% of  papillary and in &gt;80% of sessile tumors</li>
                </ul>
              </li>
              <li><strong>CIS of the upper tract is associated with higher risk for disease  progression</strong> (similar to bladder cancer) and a likelihood of future development of invasive urothelial  cancers.</li>
            </ul>
          </li>
          <li><strong>Size</strong>
            <ul>
              <li>Tumours &gt; 3-4  cm may be associated with worse survival as well as a higher risk of bladder  recurrence</li>
            </ul>
          </li>
          <li><strong><span class="red">Location</span></strong>              
            <ul>
              <li><strong><span class="red">Renal pelvic tumours are usually more aggressive than ureteral tumours</span></strong>
                <ul>
                  <li><strong><span class="red">50-60%  of renal pelvic tumors are invasive </span></strong>into  either the lamina propria or muscle,<strong> in</strong> <strong>contrast to most bladder  tumors, which are usually non-invasive</strong></li>
                  <li><strong><span class="red">55-75%  of ureteral tumors are low grade and low stage</span></strong><strong>,  but invasion is still more common than bladder tumors</strong></li>
                  <li>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 </li>
                </ul>
              </li>
              <li><strong>Conflicting  results on whether the location of an upper tract tumor affects prognosis</strong></li>
            </ul>
          </li>
          <li><strong>Multifocality</strong>
            <ul>
              <li>Defined as presence of  tumor in ≥2 sites within urothelium</li>
              <li>Independent predictor of poor clinical outcome</li>
            </ul>
          </li>
          <li><strong>Tumour  necrosis</strong>
            <ul>
              <li>Conflicting evidence on the influence of tumour necrosis on survival          </li>
            </ul>
          </li>
          <li><strong>Lymph node  involvement</strong>
            <ul>
              <li>Although  lymphadenectomy is seldom performed for clinically node-negative disease, <strong>pathologic  lymph node status is a strong predictor of post-nephroureterectomy recurrence</strong></li>
            </ul>
          </li>
          <li>LVI
            <ul>
              <li>Associated with  worse survival in patients without positive nodes; no association in N+ disease</li>
            </ul>
          </li>
          <li>Hydronephrosis
            <ul>
              <li>Independently  associated with advanced disease stage and poor survival </li>
            </ul>
          </li>
          <li>Positive  surgical margins</li>
          <li>Previous  or concomitant bladder tumours</li>
        </ul>
      </li>
      <li><strong>Patient  factors</strong>
        <ul>
          <li>Age
            <ul>
              <li>Increasing age  associated with worse survival</li>
            </ul>
          </li>
          <li>Race
            <ul>
              <li>Black  non-Hispanic race is associated with increased mortality</li>
            </ul>
          </li>
        </ul>
      </li>
      <li><strong>Surgical  factors</strong>
        <ul>
          <li>Lack  of post-operative mitomycin C instillation</li>
        </ul>
      </li>
      <li><strong><span class="red">2021 EAU  risk-stratification in UTUC:</span></strong>
        <ul>
          <li><strong><span class="red">Low-risk (5):</span></strong>
            <ol>
              <li><strong>Unifocal disease</strong></li>
              <li><strong>Tumour size &lt; 2 cm</strong></li>
              <li><strong>Negative for high-grade cytology</strong></li>
              <li><strong>Low-grade URS biopsy</strong></li>
              <li><strong>No invasive aspect on CT</strong></li>
            </ol>
          </li>
          <li><strong><span class="red">High-risk (8):</span></strong>
            <ol>
              <li>Multifocal disease</li>
              <li>Tumour size &ge; 2 cm</li>
              <li>High-grade cytology</li>
              <li>High-grade URS biopsy</li>
              <li>Hydronephrosis</li>
              <li>Previous radical cystectomy for high-grade bladder cancer</li>
              <li>Variant histology</li>
              <li>Local invasion on CT</li>
            </ol>
          </li>
        </ul>
      </li>
      <li>Clinical  prediction tools have been developed for risk stratification before and after definitive  therapy</li>
      
      <li><strong>3 particular  forms of UTUC,</strong> 2 associated with environmental  exposure (<strong>aristolochic acid nephropathy</strong>, which includes Balkan and  Chinese herbal nephropathy, as well as those seen in arsenic-endemic regions), <strong>analgesic  abuse, and those associated with Lynch syndrome, have an even higher tendency  have multiple and bilateral recurrences than do sporadic tumors</strong></li>
      <li>5-year overall  survival rates:</li>
      <ul>
        <li>Grade </li>
        <ul>
          <li>1-2:  40-87%</li>
          <li>3-4:  0-33%</li>
        </ul>
        <li>Stage</li>
        <ul>
          <li>Ta,  T1, CIS: 60-90%</li>
          <li>T2:  43-75%</li>
          <li>T3:  16-33%</li>
          <li>T4:  0-5%</li>
          <li>N+:  0-4%</li>
          <li>M+:  0%</li>
        </ul>
      </ul>
    </ul>
	<h5><span class="red"><a name="management">Management</a></span></h5>
    <ul>
      <li>As of April 2021, there were only <a href="https://uroweb.org/guideline/upper-urinary-tract-urothelial-cell-carcinoma/">EAU guidelines on Upper Tract Urothelial Carcinoma</a>. None available from AUA, CUA, or NCCN.</li>
    </ul>
    <p>&nbsp;</p>
    <ul>
      <li><strong><span class="red">Non-metastatic disease</span></strong>
        <ul>
          <li><strong><span class="red">Options:</span></strong> 
            <ol>
              <li><strong><span class="red">Radical  nephroreterectomy</span></strong> <strong><span class="red">with bladder cuff excision</span></strong></li>
              <li><strong><span class="red">Nephron-sparing approaches</span></strong>
                <ol>
                  <li><strong><span class="red"> Endoscopic ablation/resection</span></strong>
                    <ol>
                      <li>Ureteroscopic</li>
                      <li>Percutaneous                </li>
                    </ol>
                  </li>
                  <li><strong><span class="red">Segmental ureterectomy</span></strong></li>
                  <li><strong><span class="red">Intraluminal therapy</span></strong></li>
                </ol>
              </li>
            </ol>
          </li>
        </ul>
      </li>
    </ul>
    <p>&nbsp;</p>
    <ul>
      <ul>
        <li>
          <p><strong><span class="red">EAU Guideline Recommendations based on risk-stratification (see above)</span></strong>
          </p>
          <ul>
            <li>
              <p><strong><span class="red">Low-risk</span></strong>
              </p>
              <ul>
                <li><strong><span class="red">Nephron-sparing approaches recommended for ALL low-risk UTUC, </span></strong>irrespective of the status of the contralateral kidney                </li>
                <ul>
                  <li> Reduces morbidity associated with radical surgery without compromising oncological outcomes</li>
                  <li>Note that  2013 CUA Upper Tract Surveillance Guidelines described radical nephrouretectomy with bladder cuff excision as the gold standard management for non-metastatic UTUC</li>
                </ul>
                <li><strong>Radical nephroureterectomy with bladder cuff excision may be considered for large, multifocal, or rapidly recurring tumours, or tumours that have failed maximal efforts are conservative surgery</strong></li>
              </ul>
            </li>
            <li><strong><span class="red">High-risk </span></strong>
              <ul>
                <li><strong><span class="red">Radical nephrouretectomy with bladder  cuff excision +/- chemotherapy</span></strong>
                  <ul>
                    <li><strong><span class="red">Also used for low-grade,  non-invasive tumors of the renal pelvis and upper ureter when they are large,  multifocal, or rapidly recurring despite maximal efforts at conservative  surgery</span></strong></li>
                  </ul>
                </li>
                <li><strong><span class="red">Nephron-sparing approaches may be considered in select patients with:</span></strong>
                  <ul>
                    <li><strong><span class="red">Renal insuffiency (functionally or anatomically)</span></strong>
                      <ul>
                        <li><strong>Radical  nephroureterectomy and dialysis still offer the best chance of cure and  survival in patients with a large, invasive, high-grade, organ-confined renal  pelvis tumor (T2N0M0) in a solitary kidney.</strong>
                          <ul>
                            <li>For a patient with significant life expectancy, the risks and  morbidity on hemodialysis are less than the risks of an inadequately treated aggressive high-grade UTUC. </li>
                          </ul>
                        </li>
                      </ul>
                    </li>
                    <li><strong>Pre-disposition to multiple recurrences</strong></li>
                  </ul>
                </li>
                <li><strong><span class="red">In patients with radiographic  suspicion for lymph node involvement</span></strong>, the current  paradigms are shifting toward <strong><span class="red">primary treatment with  platinum-based neoadjuvant chemotherapy with surgical consolidation offered only  if a significant response is seen</span></strong></li>
              </ul>
            </li>
          </ul>
        </li>
      </ul>
    </ul>
    <p>&nbsp;</p>
    <ul>
      <ul>
        <li><strong><span class="red">Nephron-sparing  approaches (3): </span></strong>
          <ol>
            <li><strong><span class="red">Endoscopic</span></strong></li>
            <li><strong><span class="red">Segmental ureterectomy</span></strong></li>
            <li><strong><span class="red">Intraluminal therapy</span></strong></li>
          </ol>
        </li>
      </ul>
      <p>&nbsp;</p>
      <ul>
        <ul>
          <li><strong><span class="purple">Systematic review and meta-analysis comparing nephon-sparing approach to radical nephroureterectomy (2016)</span></strong>
            <ul>
              <li>Primary outcome: cancer-specific survival</li>
              <li>Results
                <ul>
                  
                  <li>Included 22 studies published between 1999 and 2015
                    <ul>
                      <li>No   RCTs comparing nephron-sparing approach and nephroureterectomy</li>
                    </ul>
                  </li>
                  <li>High risk of bias across all domains analysed, limiting interpretation of comparisons</li>
                  <li>Segemental ureterectomy vs. RNU (10 studies): no significant difference in cancer-specific survival</li>
                  <li>Endoscopic vs. RNU
                    <ul>
                      <li>URS vs. RNU (5 studies): no significant difference in cancer-specific survival
                        <ul>
                          <li>Grade-based subgroup analyses found decreased cancer-specific survival in patients undergoing URS for high-grade disease</li>
                        </ul>
                      </li>
                      <li>Percutaneous resection vs. RNU (2 studies): conflicting findings</li>
                    </ul>
                  </li>
                </ul>
              </li>
              <li><a href="https://pubmed.ncbi.nlm.nih.gov/27477528/">Seisen, Thomas, et al.</a>"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." <em>European urology</em> 70.6 (2016): 1052-1068.</li>
            </ul>
          </li>
        </ul>
        <p>&nbsp;</p>
        <ul>
          <li>
            <p><strong><span class="red">Endoscopic Treatment</span></strong></p>
            <ul>
              <li>
                <p><strong><span class="red">Indications</span></strong></p>
                <ul>
                  <li>
                    <p><strong><span class="red">Low-grade, non-invasive  tumours that can be completely resected with this approach</span></strong>
                    </p>
                    <ul>
                      <li><strong><span class="red">Patient's with   unresectable, high grade, or invasive should proceed  immediately to nephroureterectomy, provided they are medically fit. </span></strong>                      </li>
                    </ul>
                  </li>
                </ul>
              </li>
              <li><strong>Outcomes</strong>
                <ul>
                  <li><strong><span class="purple">Systematic review of endoscopic management of UTUC (2012)</span></strong>
                    <ul>
                      <li>Results:
                        <ul>
                          <li>Included 34 studies, 22 on URS and 12 on percutaneous resection
                            <ul>
                              <li> All  were case series (level of  evidence 4), or non-randomised comparative  studies (level of evidence 3b)</li>
                            </ul>
                          </li>
                          <li>Mean sample size
                            <ul>
                              <li>URS: 33</li>
                              <li>PCN: 24</li>
                              <li>3 institutions for URS and 1 for PCN, have published outcomes on cohorts of ≥ 40 patients with &gt; 50 months follow-up, limiting generalzability</li>
                            </ul>
                          </li>
                          <li>Estimated 5-yr: 
                            <ul>
                              <li>Recurrence-free survival: 13 – 54% </li>
                              <li>Renal preservation: 85% </li>
                              <li>Cancer-specific survival: 49-89% </li>
                              <li>OS 57-75% </li>
                              <li>Recurrence-free and cancer-specific survival outcomes worsened with increasing grade</li>
                            </ul>
                          </li>
                          <li><a href="https://pubmed.ncbi.nlm.nih.gov/22471401/">Cutress, Mark L., et al.</a> "Ureteroscopic and percutaneous management of upper tract urothelial carcinoma (UTUC): systematic review." <em>BJU international</em> 110.5 (2012): 614-628.</li>
                        </ul>
                      </li>
                    </ul>
                  </li>
                  <li><strong>Given high risk of recurrence with endoscopic management, patients should be informed of the need for early second-look and stringent surveillance.</strong></li>
                  <li><strong>Risk of disease progression remains with endoscopic management due to the suboptimal performance of imaging and biopsy for risk stratification and tumour biology</strong></li>
                </ul>
              </li>
              <li><strong>Approach</strong>
                <ul>
                  <li><strong>Retrograde (ureteroscopic) vs. antegrade (percutaneous)</strong>
                    <ul>
                      <li><strong>Choice depends largely on the tumor location and  size </strong>
                        <ul>
                          <li><strong>Retrograde   preferred when tumor size, number, and  access allow complete tumor ablation. </strong></li>
                          <li><strong>Percutaneous  antegrade tumor ablation preferred when the anatomy and the tumor do not allow  complete ablation through a retrograde approach because of location (e.g., lower pole calyx or proximal ureter) or previous urinary  diversion </strong></li>
                          <li>In cases with  multifocal involvement, combined antegrade and retrograde approaches can be  considered<strong> </strong></li>
                        </ul>
                      </li>
                    </ul>
                  </li>
                  <li><strong>Retrograde  approach</strong>
                    <ul>
                      <li><strong>Advantages (2)</strong>:
                        <ol>
                          <li><strong>Lower  morbidity than percutaneous and open surgical counterparts</strong></li>
                          <li><strong>Maintenance  of a closed system</strong>
                            <ul>
                              <li><strong>Non-urothelial surfaces are not exposed to the possibility  of tumor seeding</strong></li>
                            </ul>
                          </li>
                        </ol>
                      </li>
                      <li><strong>Disadvantages  (2):</strong>
                        <ol>
                          <li><strong>Smaller  instruments required</strong>
                            <ul>
                              <li><strong>Smaller endoscopes have a smaller field of view and  working channel which limits the size of tumor that can be approached in a  retrograde fashion. These small instruments limit the accuracy of biopsies, especially  with regard to staging</strong></li>
                            </ul>
                          </li>
                          <li><strong>Some  portions of the upper urinary tract, such as the lower pole calyces, cannot be  reliably reached with working instruments.</strong></li>
                        </ol>
                      </li>
                      <li><strong>Technique </strong>
                        <ul>
                          <li>The tumor is debulked  by use of either biopsy forceps or a flat wire basket engaged adjacent to the  tumor. Next, the tumor base is treated with either electrocautery or laser  energy sources. This technique is especially useful for low-grade papillary  tumor on a narrow stalk. The specimen is sent for pathologic evaluation. </li>
                          <li>Alternatively, a  ureteroscopic resectoscope is used to remove the tumor. <strong>Only the  intraluminal tumor is resected, and no attempt is made to resect deep (beyond  the lamina propria).</strong></li>
                          <li>Electrocautery  delivered through a small Bugbee electrode (2 or 3 Fr) can be used to fulgurate  tumors. However, the variable depth of penetration can make its use in the  ureter dangerous, and circumferential fulguration should be avoided because of  the high risk of stricture formation. More recently, laser energy with either a  neodymium:yttrium-aluminum-garnet (Nd:YAG) or a holmium:YAG (Ho:YAG). </li>
                          <li>A ureteral stent  is placed for a variable duration to aid with the healing process.</li>
                        </ul>
                      </li>
                    </ul>
                  </li>
                  <li><strong>Antegrade  approach</strong>
                    <ul>
                      <li><strong>Advantages (4): </strong>
                        <ol>
                          <li><strong>Ability  to use larger instruments that can remove a large volume of tumor in any  portion of the renal collecting system</strong></li>
                          <li><strong>Improved  tumour staging and grading because deeper biopsy specimens are obtained</strong></li>
                          <li><strong>May  avoid the limitations of flexible ureteroscopy, especially in complicated  calyceal systems or areas difficult to access, such as the lower pole calyx or  the upper urinary tract of patients with urinary diversion. </strong></li>
                          <li><strong>The  established nephrostomy tract can be maintained for immediate postoperative  nephroscopy and administration of topical adjuvant therapy</strong></li>
                        </ol>
                      </li>
                      <li><strong>Disadvantages  (4):</strong>
                        <ol>
                          <li><strong>Increased  morbidity compared with ureteroscopy </strong></li>
                          <li><strong>Risk  of nephrostomy tract insertion</strong></li>
                          <li><strong>Procedure  usually requires inpatient admission</strong></li>
                          <li><strong>Potential  for tumor seeding outside the urinary tract; tract seeding is a possibility but  appears to be an uncommon event</strong></li>
                        </ol>
                      </li>
                    </ul>
                  </li>
                  <li><strong>Technique</strong> [Further details in Campbell&rsquo;s]
                    <ul>
                      <li><strong>Regardless of  approach, a nephrostomy tube is left in place.</strong> This access can be used for second-look follow-up nephroscopy to ensure  complete tumor removal. Follow-up (second-look) nephroscopy is performed 4-14  days later to allow adequate healing. The tumor resection site is identified,  and any residual tumor is removed. </li>
                      <li>Complications  from percutaneous management of tumors are similar to those for benign renal  processes and include bleeding, systemic absorption of hypo-osmotic irrigation  (with monopolar resection), perforation of the collecting system, and secondary  ureteropelvic junction obstruction.</li>
                    </ul>
                  </li>
                </ul>
              </li>
            </ul>
          </li>
        </ul>
        <p>&nbsp;</p>
        <ul>
          <li><strong><span class="red">Segmental ureterectomy</span></strong>
            <ul>
              <li><strong><span class="red">Indications  (2):</span></strong>
                <ol>
                  <li><strong><span class="red">Low-grade,  low-stage tumors that are not able to be removed endoscopically</span> because of  tumor size or multiplicity</strong></li>
                  <li><strong><span class="red">High-grade  or invasive tumors when preservation of renal unit is necessary</span></strong></li>
                </ol>
              </li>
              <li><strong>Outcomes</strong>
<ul>
                  <li><strong><span class="purple">Systematic review and meta-analysis  comparing segmental resection to radical nephroureterectomy  (2020)</span></strong>
                    <ul>
                      <li>Results:
                        <ul>
                          <li>Included 18 studies comprising 4797 patients, of which 1313 underwent segementsl resection</li>
                          <li>High risk of bias across all domains analysed, limiting interpretation of comparisons</li>
                          <li>5-yr:
                            <ul>
                              <li>Recurrence-free survival: significantly worse with segemental resection</li>
                              <li>Cancer-specific survival: no significant difference</li>
                              <li>OS: no significant difference</li>
                            </ul>
                          </li>
                          <li><a href="https://pubmed.ncbi.nlm.nih.gov/31704265/">Veccia, Alessandro, et al.</a>"Segmental ureterectomy for upper tract urothelial carcinoma: a systematic review and meta-analysis of comparative studies." <em>Clinical genitourinary cancer</em> 18.1 (2020): e10-e20.</li>
                        </ul>
                      </li>
                    </ul>
                  </li>
                  <li>The  documented risk of wound implantation by tumor is low after open segemental ureterectomy if simple precautions are followed to minimize spillage</li>
                  <li>Segmental ureterectomy of the proximal two-thirds of urter is associated with higher failure rates than for the distal ureter.</li>
                </ul>
              </li>
              <li>Technique
                <ul>
                  <li>See <a href="segurerectomy.html">Segmental Ureterectomy</a> Chapter Notes for technical aspects </li>
                </ul>
              </li>
            </ul>
          </li>
        </ul>
        <p>&nbsp;</p>
        <ul>
			<li><strong><span class="red">Intraluminal therapy</span></strong>
            <ul>
              <li><strong>Used in 3  settings for treatment of UTUC:</strong>
                <ol>
                  <li><strong>Primary  treatment for CIS </strong></li>
                  <li><strong>Adjuvant therapy  after endoscopic or organ-sparing therapy</strong>              </li>
                  <li><strong>Primary treatment of low-grade UTUC (UGN-101)</strong></li>
                </ol>
              </li>
              <li><strong><span class="red">Management of Positive  Upper Tract Urinary Cytology or Carcinoma in Situ</span></strong>
                <ul>
                  <li><strong><span class="red">Diagnosis and Evaluation</span></strong>
                    <ul>
                      <li><strong><span class="red">First,  repeat the cytology to confirm the findings</span></strong>
                        <ul>
                          <li><strong>Any  source of inflammation, such as urinary infection or calculus, may produce a  false-positive result </strong></li>
                          <li>A  subsequent cytologic abnormality from the contralateral side during follow-up  is not rare in cases of true-positive results from early CIS</li>
                        </ul>
                      </li>
                      <li><strong><span class="red">Next, radiographic evaluation of the upper tracts, usually with CT  urography, and a complete bladder evaluation with cystoscopy</span></strong>
                        <ul>
                          <li><strong><span class="red">If  the bladder evaluation was </span></strong>
                            <ul>
                              <li><strong><span class="red">Positive for bladder tumour, treat the bladder</span> and follow the voided urinary cytologies. </strong>
                                <ul>
                                  <li>If cytology remains positive despite a negative bladder evaluation or after  successful treatment of the bladder,  proceed to evaluating  extravesical sites. </li>
                                </ul>
                              </li>
                              <li><strong><span class="red">Negative for bladder tumour, evaluate extravesical sites.</span></strong>
                                <ul>
                                  <li><strong> Evaluation of extravesical sites should include <span class="red">selective  cytologies from each upper urinary tract,</span></strong> ensuring non-contamination of the specimen from the bladder or urethra, <strong>as  well as resection of a representative <span class="red">specimen of the prostatic urethra in men</span></strong>.
                                    <ul>
                                      <li>Selective cytologies should preferably be done, along with ureteroscopy, to  allow for direct visualization of the upper urinary tracts.<strong></strong></li>
                                    </ul>
                                  </li>
                                  <li><strong>In  cases of unilateral upper tract cytologic abnormalities</strong> (with normal cystoscopy, pyelography, and bladder biopsies), <strong>ureteropyeloscopy  is indicated as the next step</strong>.
                                    <ul>
                                      <li>Ureteropyeloscopy allows for direct  visualization of small lesions and is superior to retrograde pyelography in the  detection of small tumors. </li>
                                      <li><strong>Biopsy at the time of ureteropyeloscopy should be  attempted, if feasible. A persistently abnormal cytology without any visualized  lesions may signify CIS</strong>.</li>
                                    </ul>
                                  </li>
                                </ul>
                              </li>
                            </ul>
                          </li>
                        </ul>
                      </li>
                    </ul>
                  </li>
                  <li><strong><span class="red">CIS of  the Upper Urinary Tracts</span></strong>
                    <ul>
                      <li><strong>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. </strong>
                        <ul>
                          <li>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</li>
                        </ul>
                      </li>
                      <li><strong> Management</strong>
                        <ul>
                          <li><strong>Not  well established</strong></li>
                          <li><strong><span class="red">Current approaches for presumed upper tract CIS include t</span></strong><strong><span class="red">opical  immunotherapy or chemotherapy</span></strong>
                            <ul>
                              <li><strong>Most  experience is from use of BCG via a nephrostomy tube for primary treatment of  CIS.</strong>
                                <ul>
                                  <li><strong><span class="purple">Systematic review and meta-analysis evaluating intraluminal therapy for UTUC (2019)</span></strong>
                                    <ul>
                                      <li>Inclusion criteria: studies evaluating patients with upper tract urothelial carcinoma receiving instillation treatment as adjuvant/curative therapy for pTa/pT1 and CIS, respectively.</li>
                                      <li>Studies with ≥10 participants included in quantitative analyses </li>
                                      <li>Results
                                        <ul>
                                          <li>Included 226 patients from 15 studies of patients that underwent BCG instillation for CIS </li>
                                          <li>Recurrence-free survival: 84% </li>
                                          <li>Cancer-specific survival: 34%</li>
                                          <li>Overall survival: 16%</li>
                                          <li>No difference in survival based on approach (antegrade, retrograde, or combined) or drug (MMC vs. BCG)</li>
                                        </ul>
                                      </li>
                                      <li><a href="https://pubmed.ncbi.nlm.nih.gov/30846387/">Foerster, Beat, et al.</a> "Endocavitary treatment for upper tract urothelial carcinoma: a meta-analysis of the current literature." <em>Urologic Oncology: Seminars and Original Investigations</em>. Vol. 37. No. 7. Elsevier, 2019.</li>
                                    </ul>
                                  </li>
                                </ul>
                              </li>
                              <li>Historically, <strong><span class="red">radical nephroureterectomy</span></strong> was performed for a unilateral cytologic abnormality of the upper tract  to eliminate presumed CIS. This practice <strong><span class="red">is not  recommended</span></strong> in the absence of any histologic, radiographic, or  endoscopic finding <strong>owing to the limitations of cytology alone with  false-positive results and the high risk for bilateral disease in the future</strong></li>
                              <li><strong>Observation is  also not appropriate without further evaluation given the repeated abnormal  cytologies. </strong></li>
                            </ul>
                          </li>
                        </ul>
                      </li>
                      <li>Another scenario  is CIS of ureteral margins during radical cystectomy. There is controversy over  the management of this finding </li>
                    </ul>
                  </li>
                </ul>
              </li>
				<li><strong><span class="red">UGN-101</span></strong> (also known as Mitogel, Jelmyto)
                <ul>
                  <li><strong name="olympus"><span class="purple"><a name="olympus">OLYMPUS (Lancet Onc 2020</a></span></strong>)
                    <ul>
                      <li>Objective: evaluate the safety and activity of UGN-101 to treat primary and recurrent low-grade UTUC.</li>
                      <li><strong>Design: open-label, single-arm, phase 3 trial</strong></li>
                      <li><strong>Population: 71 patients with primary or recurrent biopsy-proven, low-grade UTUC (involving the renal pelvis or calyces) and &ge;1 low-grade lesion above the ureteropelvic 
                        junction, measuring 
                        5–15 mm.</strong>
                        <ul>
                          <li>Lesions &gt;15 mm were 
                            eligible for endoscopic downsizing 
                            before the initiation of<br>
                            treatment.</li>
                        </ul>
                      </li>
                      <li>Treatment: 6 once-weekly treatments 
                        of UGN-101</li>
                      <li><strong>Primary outcome: complete response,</strong> defined as
                        <ul>
                          <li>Negative endoscopic examination AND</li>
                          <li>Negative cytology at the primary disease evaluation AND</li>
                          <li>Negative for-cause biopsy when done</li>
                        </ul>
                      </li>
                      <li><strong>Results:
                        </strong>
                        <ul>
                          <li><strong>Primary outcome:
                            </strong>
                            <ul>
                              <li><strong>59% complete response at 3 months</strong></li>
                              <li>48% complete response at 12 months<a href="https://www.urotoday.com/conference-highlights/suo-2020/suo-2020-gu-malignancies-non-prostate/126405-suo-2020-durability-of-response-to-chemoablative-treatment-of-low-grade-upper-tract-urothelial-carcinoma-with-a-mitomycin-containing-reverse-thermal-hydrogel-final-results-of-the-olympus-study.html">§</a></li>
                            </ul>
                          </li>
                          <li>Adverse events
                            <ul>
                              <li>Common; 94% had any adverse event</li>
                              <li>37% had ≥1 serious adverse event
                                <ul>
                                  <li>43% ureteric stenosis </li>
                                  <li>20% renal dysfunction</li>
                                </ul>
                              </li>
                            </ul>
                          </li>
                        </ul>
                      </li>
                      <li><a href="https://pubmed.ncbi.nlm.nih.gov/32631491/">Kleinmann, Nir, et al.</a> "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." <em>The lancet oncology</em> 21.6 (2020): 776-785.</li>
                    </ul>
                  </li>
                </ul>
              </li>
              <li><strong>Approaches: </strong>
                <ul>
                  <li><strong>Antegrade via percutaneous nephrostomy</strong></li>
                  <li><strong>Retrograde through a single J open-ended ureteric stent</strong>
                    <ul>
                      <li><strong>Suboptimal because the drug often does not reach the renal pelvis</strong></li>
                    </ul>
                  </li>
                  <li>Both the antegrade
                    and retrograde approach can be dangerous due to possible ureteric obstruction and consecutive pyelovenous
                    influx during instillation/perfusion. </li>
                </ul>
              </li>
              </ul>
          </li>
        </ul>
      </ul>
    </ul>
    <p>&nbsp;</p>
    <ul>
      <ul>
        <li><strong><span class="red">Radical  nephroreterectomy with bladder cuff excision</span></strong></li>
        
        <ul>
          <li>Outcomes largely dependent on  clinicopathologic characteristics.</li>
          <li>See <a href="nephroux.html">Nephroureterectomy</a> Chapter Notes for technical aspects</li>
          <li><strong>Lymphadenectomy</strong>
            <ul>
              <li><strong>Prospective  studies are needed to assess the role of lymphadenectomy in UTUC.</strong> </li>
              <li><strong>There may be prognostic and therapeutic value  in patients with invasive disease (T2 to T4),</strong> and extended lymphadenectomy  is beneficial for accurate staging.      </li>
            </ul>
          </li>
        </ul>
      </ul>
    </ul>
    <p>&nbsp;</p>
    <ul>
      <li><strong><span class="red">Adjuvant therapy</span></strong>      
        <ul>
          <li><strong><span class="red">After nephron-sparing  therapy</span></strong>
            <ul>
              <li><strong>Nephron-sparing approaches are associated with high risk of local recurrence</strong>; <strong>patients need to be followed vigilantly for disease  progression.</strong>
              </li>
            </ul>
          </li>
          <ul>
            <li><strong><span class="red">Options:</span></strong>
              <ol>
                <li><strong><span class="red">Intraluminal/instillation therapy (immuno- or chemotherapy) </span></strong></li>
                <li><strong><span class="red">Brachytherapy of the nephrostomy tract</span></strong></li>
              </ol>
            </li>
            <li><strong>Intraluminal  therapy</strong>
              <ul>
                <li>Treatment  agents include thiotepa, mitomycin, and BCG</li>
                <li>Systematic review and meta-analysis (2019)
                  <ul>
                    <li>Inclusion criteria: studies evaluating patients with upper tract urothelial carcinoma receiving instillation treatment as adjuvant/curative therapy for pTa/pT1 and CIS, respectively.</li>
                    <li>Studies with ≥10 participants included in quantitative analyses </li>
                    <li>Results
                      <ul>
                        <li>Included 212 patients from 12 studies of patients that underwent endoscopic laser ablation and instillation therapy for Ta/T1 UTUC </li>
                        <li>Recurrence-free survival: 40%
                          <ul>
                            <li>Similar to recurrence-free survival with observation after nephron-sparing surgery</li>
                          </ul>
                        </li>
                        <li>Cancer-specific survival: 94%</li>
                        <li>Overall survival: 71%</li>
                        <li>No difference in survival based on approach (antegrade, retrograde, or combined) or drug (MMC vs. BCG)</li>
                      </ul>
                    </li>
                    <li><a href="https://pubmed.ncbi.nlm.nih.gov/30846387/">Foerster, Beat, et al.</a> "Endocavitary treatment for upper tract urothelial carcinoma: a meta-analysis of the current literature." <em>Urologic Oncology: Seminars and Original Investigations</em>. Vol. 37. No. 7. Elsevier, 2019.</li>
                  </ul>
                </li>
                <li><strong>The most common  complication of intraluminal/instillation therapy is bacterial sepsis</strong></li>
              </ul>
            </li>
            <li>Brachytherapy
              <ul>
                <li>Brachytherapy  to the nephrostomy tract through iridium wire or delivery system has been  described</li>
              </ul>
            </li>
          </ul>
          <li><strong><span class="red">After complete  excision</span></strong>
            <ul>
              <li><strong>Adjuvant  radiation</strong>
                <ul>
                  <li>Radical  nephroureterectomy alone provides a high rate of local control; <strong>adjuvant  radiation</strong> without chemotherapy for high-stage disease <strong>does not protect  against a high rate of distant failure</strong></li>
                  <li>Retrospective studies suggest that there  may be a role for combined radiation-chemotherapy regimens in patients with  advanced disease with adverse features</li>
                </ul>
              </li>
              <li><strong><span class="red">Adjuvant chemotherapy</span></strong>
                <ul>
                  <li><strong><span class="red">Intravesical</span></strong>
                    <ul>
                      <li><strong><span class="purple">ODMIT-C (2011)</span></strong>
                        <ul>
                          <li><strong>Population: 284  patients with no previous or concurrent history of bladder cancer undergoing  nephroureterectomy for suspected UTUC</strong></li>
                          <li><strong>Randomized to a  single postoperative intravesical dose of MMC</strong> (40 mg in 40 ml saline) <strong>at the time of urinary catheter removal</strong> <strong>vs.  standard management</strong></li>
                          <li><strong>Results:</strong>
                            <ul>
                              <li><strong>Risk  of bladder tumour in first year reduced by 11%</strong> (27% MMC vs. 16% standard treatment)</li>
                            </ul>
                          </li>
                          <li><a href="https://www.ncbi.nlm.nih.gov/pubmed/21684068">O'Brien,  Tim, et al.</a>&quot;Prevention of bladder tumours after nephroureterectomy for  primary upper urinary tract urothelial carcinoma: a prospective, multicentre,  randomised clinical trial of a single postoperative intravesical dose of  mitomycin C (the ODMIT-C Trial).&quot; European urology 60.4 (2011): 703-710.</li>
                        </ul>
                      </li>
                    </ul>
                  </li>
                  <li><strong><span class="red">Systemic </span></strong>
                    <ul>
                      <li>The use of  agents for UTUC has been extrapolated from chemotherapy regimens used in bladder  urothelial cancer</li>
                      <li>Neoadjuvant
                        <ul>
                          <li>Lack of  trials that establish the efficacy of  neoadjuvant chemotherapy for UTUC. </li>
                        </ul>
                      </li>
                      <li><strong><span class="red">Adjuvant</span></strong>
                        <ul>
                          <li><strong><span class="purple">POUT</span></strong>
                            <ul>
                              <li><strong>Population: 260  patients with histologically confirmed pT2-T4, N0-3, M0 or pTany, N+, MO UTUC</strong></li>
                              <li><strong>Randomized  to 4 cycles of gemcitabine-cisplatin</strong> (gemcitabine-carboplatin if GFR 30-49ml/min) <strong>or surveillance with subsequent  chemotherapy, if required</strong></li>
                              <li><strong>Primary outcome:  disease-free survival</strong></li>
                              <li>Secondary  endpoints included metastasis-free survival, overall survival, toxicity &amp;  quality of life</li>
                              <li><strong>Results</strong>
                                <ul>
                                  <li><strong>Trial closed  early as data met early stopping rule for efficacy</strong></li>
                                  <li>Median  follow-up: 30 months</li>
                                  <li><strong>Disease-free  survival improved by 21% at 3 years</strong> (71% chemotherapy vs. 46% surveillance; HR 0.45)</li>
                                  <li><strong>Significantly  improved metastasis-free survival; OS data not mature</strong></li>
                                  <li>Toxicity:  neutropenia, thrombocytopenia, nausea, febrile neutropenia, vomiting; QOL worse  initially with chemotherapy, similar by 6 months</li>
                                </ul>
                              </li>
                              <li><a href="https://www.ncbi.nlm.nih.gov/pubmed/32145825">Birtle,  Alison, et al.</a>&quot;Adjuvant chemotherapy in upper tract urothelial carcinoma  (the POUT trial): a phase 3, open-label, randomised controlled trial.&quot; The  Lancet (2020). <a href="https://www.ncbi.nlm.nih.gov/pubmed/32145825"></a></li>
                            </ul>
                          </li>
                          <li>A  disadvantage of adjuvant chemotherapy is that many patients have baseline  chronic kidney disease, which worsens after nephroureterectomy, rendering them  ineligible to receive the full-dose cisplatinum-based chemotherapy </li>
                        </ul>
                        <blockquote>
                          <p>&nbsp;</p>
                        </blockquote>
                      </li>
                    </ul>
                  </li>
                </ul>
              </li>
            </ul>
          </li>
        
          <li><strong>Follow-up</strong>
            <ul>
              <li>The primary aims  of postoperative surveillance for UTUC are to identify urothelial recurrences,  de novo tumours of the urinary tract, and distant metastases at early stages  when they may be amenable to treatment</li>
              <li>Post-nephroureterectomy recurrences of the
                <ul>
                  <li>Retroperitoneum or pelvis  occurr in ≈5%</li>
                  <li>Contralateral upper tract occurred in ≈2%</li>
                  <li> Port-site occur very infrequently,  usually associated  with inadvertent entry into the collecting system.</li>
                </ul>
              </li>
              <li>Distant  metastases 
                <ul>
                  <li>Occurred following nephroureterectomy in 16% of patients. </li>
                  <li>Median time to metastases was 13-16  months.</li>
                  <li>The  reported sites of metastases included retroperitoneal lymph nodes in 5%, lung  in 5%, bone in 4% and liver in 4%. Less common sites included brain, adrenal  gland and non-regional lymph nodes. </li>
                </ul>
              </li>
              <li><strong><span class="red">The  CUA surveillance protocol is based on pathologic tumour stage, pathological nodal status, grade, lymphovascular invasion status, and multifocality</span></strong>
                <ul>
                  <li><strong>See <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6114151/table/t6-cuaj-8-243/">Table</a> from 1 <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6114151/">2018 CUA Surveillance guidelines based on recurrence patterns for upper tract urothelial carcinoma</a></strong></li>
                </ul>
              </li>
              <li><strong><span class="red">Post-operative  evaluation must routinely include evaluation of the:</span></strong>
                <ol>
                  <li><strong><span class="red">Bladder</span></strong></li>
                  <li><strong><span class="red">Ipsilateral (if organ-sparing therapy was chosen) and contralateral  urinary tracts</span></strong></li>
                  <li><strong><span class="red">Extra-urinary sites for local and metastatic spread</span></strong> </li>
                </ol>
                <ul>
                  <li><strong>Bladder </strong>
                    <ul>
                      <li><strong>Should be assessed with cytology and cystoscopy </strong><strong>in  all patients at months 3, 6, 12, 18, 24 and annually thereafter for up to 10  years of recurrence-free survival</strong> </li>
                    </ul>
                  </li>
                  <li><strong><span class="red">Ipsilateral upper tract</span></strong>
                    <ul>
                      <li><strong><span class="red">Should be assessed by URS and selective cytology or  biopsy in all patients following nephron-sparing  procedures</span> at months 3, 6, 12, 18, 24 and annually thereafter up to 10  years of recurrence-free survival</strong>
                        <ul>
                          <li><strong>Most  patients following nephron-sparing procedures will develop ipsilateral upper  tract recurrences.</strong>
                            <ul>
                              <li><strong>Ipsilateral upper tract tumor usually occurs in a  proximal-to-distal direction</strong>; recurrence proximal to the original lesion is rare. </li>
                              <li><strong>This  high rate of ipsilateral recurrence results in part from a multifocal field  change, which is even more pronounced than in bladder cancer</strong></li>
                            </ul>
                          </li>
                          <li><strong><span class="red">Computed tomography urography (CTU) and retrograde pyelography lacks  sensitivity</span></strong></li>
                        </ul>
                      </li>
                    </ul>
                  </li>
                  <li><strong><span class="red">Extra-urinary sites</span></strong>
                    <ul>
                      <li><strong><span class="red">Routine  blood work should include:</span></strong><strong> </strong>
                        <ul>
                          <li><strong><span class="red">Renal function tests</span></strong><strong> </strong></li>
                          <li><strong><span class="red">Metabolic panel, including liver function tests, calcium and  alkaline phosphatase</span></strong></li>
                        </ul>
                      </li>
                      <li><strong><span class="red">To  assess for local, contralateral and distant metastases </span></strong>in  patients after nephroureterectomy or nephron-sparing procedures,<strong> <span class="red">imaging of the abdomen and pelvis with CTU is recommended</span></strong>
                        <ul>
                          <li>MRI or US may be  substituted for CTU in patients with contraindications to CTU</li>
                          <li><strong>CXR  is recommended to assess for lung metastases </strong></li>
                          <li>Bone scan is  indicated in the presence of bone pain, elevated calcium or elevated alkaline  phosphatase to assess for bone metastases </li>
                        </ul>
                      </li>
                    </ul>
                  </li>
                </ul>
              </li>
              <li><strong>Lack  of evidence for an optimal duration of surveillance;  recommended approach:</strong>
                <ul>
                  <li><strong>High-grade, pT≥2 or pN+: lifelong annual surveillance with history, physical  examination, blood work, urine cytology and abdominal/chest imaging</strong></li>
                  <li><strong>Low-grade,  pT&lt;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 </strong> </li>
                </ul>
              </li>
            </ul>
          </li>
        </ul>
      </li>
    </ul>
    <p>&nbsp;</p>
    <ul>
      <li><strong>Metastatic disease</strong> 
        <ul>
          <li>Limited  data on the efficacy of chemotherapy in metastatic UTUC
            <ul>
              <li>Prospective randomized  trials comparing chemotherapeutic regimens for UTUC are not feasible owing to  the rarity of these patients.</li>
            </ul>
          </li>
          <li><strong>Regimen: MVAC (methotrexate, vinblastine, doxorubicin  (Adriamycin), and cisplatin)</strong>
            <ul>
              <li><strong>Continues  to have the highest response rate</strong></li>
              <li><strong>Carboplatin is frequently substituted instead of cisplatin because of either limitations of renal function or concerns over  nephrotoxicity associated with cisplatin. Results with carboplatin are inferior than cisplatin.</strong></li>
            </ul>
          </li>
          <li>Complete  responses are rare in the metastatic setting, and the duration of response is  limited, with overall survival of 12-24 months    </li>
        </ul>
      </li>
    </ul>
    <h5><span class="red"><a name="questions">Questions</a></span></h5>
    <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>
	<h5><span class="red"><a name="answers">Answers</a></span></h5>
    <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>
    <p>&nbsp;</p>
<h5>References</h5>
      <ul>
        <li>Wein AJ, Kavoussi LR, Partin AW, Peters CA (eds): CAMPBELL-WALSH UROLOGY, ed 11. Philadelphia, Elsevier, 2015, vol 1, chap 58</li>
      </ul>