UTUC Unabridged FINAL 060923

Any person or company accessing this guideline with the intent of using the guideline for promotional purposes
must obtain a licensable copy.
American Urological Association (AUA)/

Society of Urologic Oncology (SUO)
A PPROVED BY THE AUA DIAGNOSIS AND MANAGEMENT OF NON-METASTATIC

B OARD OF D IRECTORS APRIL
2023 UPPER TRACT UROTHELIAL CARCINOMA:
Authors’ disclosure of potential
conflicts of interest and AUA/SUO GUIDELINE (2023)
author/staff contributions appear
at the end of the article.
© 2023 by the American Jonathan A. Coleman, MD; Peter E. Clark, MD; David I. Buckley, MD, MPH; Sam S. Chang
Urological Association MD, MBA; Roger Chou, MD; Jean Hoffman-Censits, MD; Girish S. Kulkarni, MD, PhD;
Surena F. Matin, MD; Phillip M. Pierorazio, MD; Aaron M. Potretzke, MD; Sarah P.
Psutka, MD; Jay D. Raman, MD; Angela B. Smith, MD; Laura Smith
SUMMARY
Purpose
The purpose of this guideline is to provide a useful reference on the effective evidence-based diagnoses and management
of non-metastatic upper tract urothelial carcinoma (UTUC).
Methodology
The Pacific Northwest Evidence-based Practice Center of Oregon Health & Science University (OHSU) team conducted
searches in Ovid MEDLINE (1946 to March 3rd, 2022), Cochrane Central Register of Controlled Trials (through January
2022), and Cochrane Database of Systematic Reviews (through January 2022). The searches were updated August 2022
and January 2023. When sufficient evidence existed, the body of evidence was assigned a strength rating of A (high), B
(moderate), or C (low) for support of Strong, Moderate, or Conditional Recommendations. In the absence of sufficient
evidence, additional information is provided as Clinical Principles and Expert Opinions.
GUIDELINE STATEMENTS
DIAGNOSIS AND EVALUATION
1. For patients with suspected UTUC, a cystoscopy and cross- sectional imaging of the upper tract with contrast
including delayed images of the collecting system and ureter should be performed. (Strong Recommendation;
Evidence Level: Grade B)
2. Clinicians should evaluate patients with suspected UTUC with diagnostic ureteroscopy and biopsy of any identified
lesion and cytologic washing from the upper tract system being inspected. (Strong Recommendation; Evidence
Level: Grade C)
3. In patients who have concomitant lower tract tumors (bladder/urethra) discovered at the time of ureteroscopy, the
lower tract tumors should be managed in the same setting as ureteroscopy. (Expert Opinion)
Copyright © 2023 American Urological Association Education and Research, Inc. ®

Any person or company accessing this guideline with the intent of using the guideline for promotional purposes must obtain a licensable copy.
Upper Tract Urothelial Carcinoma (UTUC)
4. In cases of existing ureteral strictures or difficult access to the upper tract, clinicians should minimize risk of ureteral
injury by using gentle dilation techniques such as temporary stenting (pre-stenting) and limit use of aggressive
dilation access techniques such as ureteral access sheaths. (Expert Opinion)
5. In cases where ureteroscopy cannot be safely performed or is not possible, an attempt at selective upper tract
washing or barbotage for cytology may be made and pyeloureterography performed in cases where good quality
imaging such as CT or MR urography cannot be obtained. (Conditional Recommendation; Evidence Level: Grade
C)
6. At the time of ureteroscopy for suspected UTUC, clinicians should not perform ureteroscopic inspection of a
radiographically and clinically normal contralateral upper tract. (Expert Opinion)
7. For patients with suspected/ diagnosed UTUC, clinicians should obtain a personal and family history to identify
known hereditary risk factors for familial diseases associated with Lynch Syndrome (LS) (colorectal, ovarian,
endometrial, gastric, biliary, small bowel, pancreatic, prostate, skin and brain cancer) for which referral for genetic
counseling should be offered. (Expert Opinion)
8. Universal histologic testing of UTUC with additional studies, such as immunohistochemical (IHC) or microsatellite
instability (MSI), should be performed to identify patients with high probability of Lynch-related cancers whom
clinicians should refer for genetic counseling and germline testing. (Strong Recommendation; Evidence Level:
Grade B)
RISK STRATIFICATION
9. At the time of identified UTUC, clinicians should perform a standardized assessment documenting clinically
meaningful endoscopic (focality, location, appearance, size) and radiographic (invasion, obstruction, and
lymphadenopathy) features to facilitate clinical staging and risk assessment. (Strong Recommendation; Evidence
Level: Grade B)
10. Following standardized assessment, clinicians should risk-stratify patients as “low-” or “high” risk for invasive
disease (pT2 or greater) based on obtained endoscopic, cytologic, pathologic, and radiographic findings. Further
stratification into favorable and unfavorable risk groups should then be based on standard identified features (Table
5). (Strong Recommendation; Evidence Level: Grade B)
11. Patients with UTUC should be assessed prior to surgery for the risk of post-NU CKD or dialysis. (Expert Opinion)
TREATMENT
12. Clinicians should provide patients with a description of the short- and long-term risks associated with recommended
diagnostic and therapeutic options. This includes the need for endoscopic follow-up, clinically significant strictures,
toxicities associated with surgical treatment and side effects from neoadjuvant and adjuvant therapies. (Clinical
Principle)
Kidney Sparing Management

13. Tumor ablation should be the initial management option for patients with LR favorable UTUC. (Strong
Recommendation; Evidence Level: Grade B)
14. Tumor ablation may be the initial management option offered to patients with LR unfavorable UTUC and select
patients with HR favorable disease who have low-volume tumors or cannot undergo RNU. (Conditional
Recommendation; Evidence Level: Grade C)

15. Tumor ablation may be accomplished via a retrograde or antegrade percutaneous approach and repeat endoscopic
evaluation should be performed within three months. (Expert Opinion)
16. Following ablation of UTUC tumors and after confirming there is no perforation of the bladder or upper tract,
clinicians may instill adjuvant pelvicalyceal chemotherapy (Conditional Recommendation; Evidence Level: Grade
C) or intravesical chemotherapy (Expert Opinion) to decrease the risk of urothelial cancer recurrence.
17. Pelvicalyceal therapy with BCG may be offered to patients with HR favorable UTUC after complete tumor ablation
or patients with upper tract carcinoma in situ (CIS). (Expert Opinion)
18. When tumor ablation is not feasible or evidence of risk group progression is identified in patients with LR UTUC,
surgical resection of all involved sites either by RNU or segmental resection of the ureter should be offered.
(Moderate Recommendation; Evidence Level: Grade C)
19. Clinicians may offer watchful waiting or surveillance alone to select patients with UTUC with significant
comorbidities, competing risks of mortality, or at significant risk of End-Stage Renal Disease (ESRD) with any
intervention resulting in dialysis. (Expert Opinion)
Surgical Management
20. Clinicians should recommend RNU or SU for surgically eligible patients with HR UTUC. (Strong Recommendation;
21. For surgically eligible patients with HR and unfavorable LR cancers endoscopically confirmed as confined to the
lower ureter in a functional renal unit, distal ureterectomy and ureteral reimplantation is the preferred treatment.
(Expert Opinion)
22. When performing NU or distal ureterectomy, the entire distal ureter including the intramural ureteral tunnel and
ureteral orifice should be excised, and the urinary tract should be closed in a watertight fashion. (Strong
Recommendation, Evidence Level: Grade B)
23. In patients undergoing RNU or SU (including distal ureterectomy) for UTUC, a single dose of perioperative
intravesical chemotherapy should be administered in eligible patients to reduce the risk of bladder recurrence.
(Strong Recommendation; Evidence Level: Grade A)
Lymph Node Dissection (LND)

24. For patients with LR UTUC, clinicians may perform LND at time of NU or ureterectomy. (Conditional
Recommendation; Evidence Level: Grade C)
25. For patients with HR UTUC, clinicians should perform LND at the time of NU or ureterectomy. (Strong
Neoadjuvant/Adjuvant Chemotherapy and Immunotherapy

26. Clinicians should offer cisplatin-based NAC to patients undergoing RNU or ureterectomy with HR UTUC, particularly
in those patients whose post-operative eGFR is expected to be less than 60 mL/min/1.73m 2 or those with other
medical comorbidities that would preclude platinum-based chemotherapy in the post-operative setting. (Strong

27. Clinicians should offer platinum-based adjuvant chemotherapy to patients with advanced pathological stage (pT2–
T4 pN0–N3 M0 or pTany N1–3 M0) UTUC after RNU or ureterectomy who have not received neoadjuvant platinum-
based therapy. (Strong Recommendation; Evidence Level: Grade A)
28. Adjuvant nivolumab therapy may be offered to patients who received neoadjuvant platinum-based chemotherapy
(ypT2–T4 or ypN+) or who are ineligible for or refuse perioperative cisplatin (pT3, pT4a, or pN+). (Conditional
29. In patients with metastatic (M+) UTUC, RNU or ureterectomy should not be offered as initial therapy. (Expert
Opinion)
30. Patients with clinical, regional node-positive (cN1-3, M0) UTUC should initially be treated with systemic therapy.
Consolidative RNU or ureterectomy with lymph-node dissection may be performed in those with a partial or
complete response. (Expert Opinion)
31. Patients with unresectable UTUC (including those who are ineligible or refuse surgery [RNU or ureterectomy])
should be offered a clinical trial or best supportive care including palliative management (radiation, systemic
approach, endoscopic, or ablative) for refractory symptoms such as hematuria. (Expert Opinion)
SURVEILLANCE AND SURVIVORSHIP

Post-Treatment Surveillance
S URVEILLANCE A FTER K IDNEY S PARING

32. Low-risk patients managed with kidney sparing treatment should undergo a follow-up cystoscopy and upper tract
endoscopy within one to three months to confirm successful treatment. Once confirmed, these patients should
undergo continued cystoscopic surveillance of the bladder at least every six to nine months for the first two years
and then at least annually thereafter. Endoscopy should be repeated at six months and one year. Upper tract
imaging should be performed at least every six to nine months for two years, then annually up to five years.
surveillance after five years in the absence of recurrence should be based on shared decision-making between the
patient and clinician. (Expert Opinion)
33. High-risk patients managed with kidney sparing treatment should undergo a follow-up cystoscopy and upper tract
endoscopy with cytology within one to three months. Patients with no evidence of disease should undergo
cystoscopic surveillance of the bladder and cytology at least every three to six months for the first three years and
then at least annually thereafter. Endoscopy should be repeated at least at six months and one year. Upper tract
imaging should be performed every three to six months for three years, then annually up to five years. surveillance
after five years in the absence of recurrence should be encouraged and based on shared decision-making between
the patient and clinician. (Expert Opinion)
34. Patients who develop urothelial recurrence in the bladder or urethra or positive cytology following treatment for
UTUC should be evaluated for possible ipsilateral recurrence or development of new contralateral upper tract
disease. (Expert Opinion)
S URVEILLANCE AFTER R ADICAL NU

35. After NU, patients with <pT2 N0/M0 disease should undergo surveillance with cystoscopy and cytology within three
months after surgery, then repeated based on pathologic grade. For LG this should repeated at least every six to
nine months for the first two years and then at least annually thereafter. For HG, this should be repeated at least
every three to six months for the first three years and then at least annually thereafter. Due to the metastasis risk
and estimated 5% probability for contralateral disease, cross-sectional imaging of the abdomen and pelvis should

be done within 6 months after surgery and then at least annually for a minimum of 5 years. Surveillance after five
years in the absence of recurrence should be encouraged and based on shared decision-making between the
patient and clinician (See Table 6). (Expert Opinion)
T2+ MANAGED WITH NU

36. For Patients who have undergone NU for >pT2 Nx/0 disease, a clinician should perform surveillance cystoscopy
with cytology at three months after surgery, then every three to six months for 3 years, and then annually thereafter.
Cross-sectional imaging of the abdomen and pelvis with multiphasic contrast-enhanced CT urography should be
performed every three to six months for years one and two, every six months at year three, and annually thereafter
to year five. A clinician should perform chest imaging, preferably with chest CT, every 6-12 months for the first 5
years. Beyond five years after surgery in patients without recurrence, ongoing surveillance with cystoscopy and
upper tract imaging may be continued on an annual basis according to principles of shared/informed decision-
making. (Expert Opinion)
Survivorship
37. For patients with reduced or deteriorating renal function following NU or other intervention, clinicians should
consider referral to nephrology. (Expert Opinion)
38. Clinicians should discuss disease-related stresses and risk factors and encourage patients with urothelial cancer
to adopt healthy lifestyle habits, including smoking cessation, exercise, and a healthy diet, to promote long-term
health benefits and quality of life. (Expert Opinion)

Search Strategy
INTRODUCTION
The Pacific Northwest Evidence-based Practice Center of
PURPOSE Oregon Health & Science University (OHSU) team
conducted searches in Ovid MEDLINE (1946 to March
Upper Tract urothelial cancer (UTUC) is a rare disease, 3rd, 2022), Cochrane Central Register of Controlled Trials
posing unique challenges to clinical management and (through January 2022), and Cochrane Database of
significant risks to patients – both from the disease and Systematic Reviews (through January 2022). The
treatment forms. UTUC is often considered analogous to searches were updated August 2022 and January 2023.
urothelial cancer of the bladder, yet pathogenic, genomic, The team developed a search strategy by using medical
biologic, and clinical distinctions between these entities subject headings terms and key words relevant to the
have been identified.1, 2 As a clinically clear example, the diagnosis and treatment UTUC. The evidence review
diagnosis of UTUC of the renal pelvis is associated with a team also reviewed relevant systematic reviews and
5-year mortality rate >50%, comparatively worse than the references provided by the Panel to identify articles that
<25% rate for bladder cancer.3 The risk of renal functional may have been missed by the database searches.
loss and associated patient morbidity places patients at
an additional clinical disadvantage, warranting Study Selection and Data Abstraction
specialized approaches and instrumentation for disease
assessment, clinical staging and management. Such Study selection was based on predefined eligibility criteria
aspects highlight the clear need for well-designed, multi- for the patient populations, interventions, outcomes, and
disciplinary strategies to guide optimal management for study designs of interest. Two reviewers independently
this vulnerable patient population to control variability and screened titles, abstracts, and full text for inclusion.
reduce the risks from under- and over-treatment. Differences between reviewers regarding eligibility were
Emerging data from standardized paradigms for resolved through consensus.
evaluation, counseling, and management provide a basis
for appropriate risk stratified approaches to optimize Assessment of Risk of Bias (ROB) of
patient care, limit toxicity, and improve cancer control and Individual Studies
survival. Curation and dissemination of this information,
especially in a rare disease prone to clinical complexity, Two investigators independently assessed ROB using
is critical to well-informed patient care and the predefined criteria. Disagreements were resolved by
consideration for referral to experienced, multi- consensus. For randomized trials and cohort studies,
disciplinary teams in more challenging cases. criteria for assessing ROB were adapted from the U.S.
Preventive Services Task Force.4 Criteria for randomized
METHODOLOGY trials included use of appropriate randomization and
allocation concealment methods, baseline comparability
Panel Formation and Process of groups, blinding, attrition, and use of intention-to-treat
analysis. For cohort studies on prognostic factors, criteria
The UTUC Panel was created in 2021 by the American included methods for assembling cohorts, attrition,
Urological Association Education and Research, Inc. blinding assessment of outcomes, and adjustment for
(AUAER) to develop a clinical guideline addressing potential confounding. Systematic reviews were
management of localized or regionally advanced UTUC. assessed using AMSTAR 2 (Assessing the
This guideline was developed in collaboration with the Methodological Quality of Systematic Reviews) criteria. 5
Society of Urologic Oncology (SUO). The Practice Criteria included use of pre-specified methods,
Guidelines Committee (PGC) of the AUA selected the appropriate search methods, assessment of risk of bias,
Panel Chair who in turn appointed the additional panel and appropriate synthesis methods. Studies were rated
members based on an open nomination process. The as “low ROB,” “moderate ROB,” or “high ROB” based on
Panel included specialists from urology and oncology. the presence and seriousness of methodological

shortcomings. The evidence review team graded strength strength as Grade A (well-conducted and highly-
of evidence on outcomes by adapting the AUA’s three generalizable randomized control trial (RCTs) or
predefined levels (A, B, or C) of strength of evidence. exceptionally strong observational studies with consistent
findings), Grade B (RCTs with some weaknesses of
Determination of Evidence Strength procedure or generalizability or moderately strong
observational studies with consistent findings), or Grade
The categorization of evidence strength is conceptually C (RCTs with serious deficiencies of procedure or
distinct from the quality of individual studies. Evidence generalizability or extremely small sample sizes or
strength refers to the body of evidence available for a observational studies that are inconsistent, have small
particular question and includes not only the quality of sample sizes, or have other problems that potentially
individual studies but consideration of study design; confound interpretation of data). By definition, Grade A
consistency of findings across studies; adequacy of evidence has a high level of certainty, Grade B evidence
sample sizes; and generalizability of study populations, has a moderate level of certainty, and Grade C evidence
settings, and interventions for the purposes of the has a low level of certainty (Table 1).6
guideline. The AUA categorizes body of evidence
Table 1: Strength of Evidence Definitions

AUA Strength of GRADE Certainty Definition
Evidence Category Rating
A High  Very confident that the true effect lies close to that of the estimate of
the effect
B Moderate  Moderately confident in the effect estimate

 The true effect is likely to be close to the estimate of the effect, but
there is a possibility that it is substantially different
C Low  Confidence in the effect estimate is limited

 The true effect may be substantially different from the estimate of the
effect
Very Low  Very little confidence in the effect estimate

 The true effect is likely to be substantially different from the estimate
of effect
AUA Nomenclature: Linking Statement Type outweigh risks/burdens) or should not (risks/burdens
to Evidence Strength outweigh benefits) be undertaken because net benefit or
net harm is moderate. Conditional Recommendations
The AUA nomenclature system explicitly links statement are non-directive statements used when the evidence
type to body of evidence strength, level of certainty, indicates there is no apparent net benefit or harm or when
magnitude of benefit or risk/burdens, and the Panel’s the balance between benefits and risks/burden is unclear.
judgment regarding the balance between benefits and All three statement types may be supported by any body
risks/burdens (Table 2). Strong Recommendations are of evidence strength grade. Body of evidence strength
directive statements that an action should (benefits Grade A in support of a Strong or Moderate
outweigh risks/burdens) or should not (risks/burdens Recommendation indicates the statement can be applied
outweigh benefits) be undertaken because net benefit or to most patients in most circumstances and that future
net harm is substantial. Moderate Recommendations research is unlikely to change confidence. Body of
are directive statements that an action should (benefits evidence strength Grade B in support of a Strong or

Moderate Recommendation indicates the statement can of the document for review. The guideline was also sent
be applied to most patients in most circumstances, but to the Urology Care Foundation and the AUA Public
better evidence could change confidence. Body of Policy & Advocacy team to open the document further to
evidence strength Grade C in support of a Strong or the patient perspective. The draft guideline document was
Moderate Recommendation indicates the statement can distributed to 114 peer reviewers. All peer review
be applied to most patients in most circumstances, but comments were blinded and sent to the Panel for review.
better evidence is likely to change confidence. Body of In total, 46 reviewers provided comments, including 34
evidence strength Grade C is only rarely used in support external reviewers. At the end of the peer review process,
of a Strong Recommendation. Conditional a total of 681 comments were received. Following
Recommendations can also be supported by any comment discussion, the Panel revised the draft as
evidence strength. When body of evidence strength is needed. Once finalized, the guideline was submitted for
Grade A, the statement indicates benefits and approval to the AUA PGC, SQC, and BOD for final
risks/burdens appear balanced, the best action depends approval.
on patient circumstances, and future research is unlikely
to change confidence. When body of evidence strength BACKGROUND
Grade B is used, benefits and risks/burdens appear
balanced, the best action also depends on individual UTUC refers to urothelial tumors that originate from the
patient circumstances, and better evidence could change inner lining of the ureter, calyces, or renal pelvis.7 These
confidence. When body of evidence strength Grade C is anatomic structures derive embryologically from
used, there is uncertainty regarding the balance between mesoderm and the ureteric bud associated with the
benefits and risks/burdens, alternative strategies may be wolffian duct, separate and distinct from the bladder and
equally reasonable, and better evidence is likely to urethra, which are endodermal structures developed from
change confidence. the cloaca. Although related in pathogenesis to lower tract
urothelial cancer (bladder and urethra), UTUC is much
Where gaps in the evidence existed, Clinical Principles or less common, only affecting 5-10% of all patients with
Expert Opinions are provided via consensus of the Panel. urothelial carcinoma though poorly documented such that
A Clinical Principle is a statement about a component of true estimates of incidence are difficult to track.8
clinical care widely agreed upon by urologists or other According to the American Cancer Society, approximately
clinicians for which there may or may not be evidence in 4,010 Americans will be diagnosed with cancer of the
the medical literature. Expert Opinion refers to a ureter/other urinary organs in 2022. Surveillance,
statement based on members' clinical training, Epidemiology, and End Results (SEER) estimates report
experience, knowledge, and judgment for which there a consistent incidence of renal pelvic tumors between 0.9
may or may not be evidence in the medical literature. - 1.0 cases per 100,000 in the U.S. through 2019,
equaling between 2,980-3,280 cases per year.7 Together,
Peer Review and Document Approval these data indicate an estimated total incidence of UTUC
of just over 7,000 U.S. cases per year – slightly less than
An integral part of the guideline development process at
the annual incidence of testis cancer (8,000 – 10,000
the AUA is external peer review. The AUA conducted a
cases).
thorough peer review process to ensure that the
document was reviewed by experts in the diagnosis and As a rare disease with complex management paradigms,
treatment of UTUC. In addition to reviewers from the AUA clinicians should have knowledge of patient
PGC, Science and Quality Council (SQC), and Board of demographics, staging distribution and causative factors
Directors (BOD), the document was reviewed by when evaluating patients with suspected UTUC.
representatives from the American Society of Clinical According to SEER population data, approximately 25%
Oncology (ASCO), American Society for Radiation of cases will present as localized disease, over 50% will
Oncology (ASTRO), and SUO as well as external content have regionally advanced cancers, and nearly 20% will
experts. Additionally, a call for reviewers was placed on have distant disease at the time of diagnosis. Peak
the AUA website from November 18- December 2, 2022, incidence is seen in adults aged >70 years and is three
to allow any additional interested parties to request a copy times more common in men than women in western

countries.3, 9 Risk factors include occupational exposure, upper tract inflammation, and hereditary factors such as
geographic location, Balkan endemic nephropathy Lynch and Lynch-like syndromes.10
associated with aristolochia herbal ingestion, chronic
Table 2: AUA Nomenclature Linking Statement Type to Level of Certainty, Magnitude of Benefit or
Risk/Burden, and Body of Evidence Strength
Evidence Grade Evidence Strength A Evidence Strength B Evidence Strength C
(High Certainty) (Moderate Certainty) (Low Certainty)
Strong -Benefits > Risks/Burdens (or -Benefits > Risks/Burdens (or -Benefits > Risks/Burdens (or vice
Recommendation vice versa) vice versa) versa)
(Net benefit or -Net benefit (or net harm) is -Net benefit (or net harm) is -Net benefit (or net harm) appears
harm substantial) substantial substantial substantial
-Applies to most patients in -Applies to most patients in -Applies to most patients in most
most circumstances and future most circumstances but better circumstances but better evidence
research is unlikely to change evidence could change is likely to change confidence
confidence confidence (rarely used to support a Strong
Recommendation)
Moderate -Benefits > Risks/Burdens (or -Benefits > Risks/Burdens (or -Benefits > Risks/Burdens (or vice
Recommendation vice versa) vice versa) versa)
(Net benefit or -Net benefit (or net harm) is -Net benefit (or net harm) is -Net benefit (or net harm) appears
harm moderate) moderate moderate moderate
-Applies to most patients in -Applies to most patients in -Applies to most patients in most
most circumstances and future most circumstances but better circumstances but better evidence
research is unlikely to change evidence could change is likely to change confidence
confidence confidence
Conditional -Benefits = Risks/Burdens -Benefits = Risks/Burdens -Balance between Benefits &

Recommendation -Best action depends on -Best action appears to depend Risks/Burdens unclear
(Net benefit or individual patient on individual patient -Net benefit (or net harm)
harm comparable to circumstances circumstances comparable to other options
other options) -Future Research is unlikely to -Better evidence could change -Alternative strategies may be
change confidence confidence equally reasonable
-Better evidence likely to change
confidence
Clinical Principle a statement about a component of clinical care that is widely agreed upon by urologists or other clinicians
for which there may or may not be evidence in the medical literature
Expert Opinion a statement, achieved by consensus of the Panel, that is based on members' clinical training, experience,
knowledge, and judgment for which there may or may not be evidence in the medical literature

diagnostic accuracy of US for UTUC alone, one study of

Guideline Statements 575 patients evaluated the accuracy of US (followed by
CT only if US was suspicious) for the diagnosis of upper
DIAGNOSIS AND EVALUATION urinary tract malignancies (renal cell carcinoma or UTUC)
in a population with hematuria.13 In this cohort, US was
1. For patients with suspected UTUC, a cystoscopy associated with high sensitivity (100%) and specificity
and cross- sectional imaging of the upper tract (97%) for upper tract malignancies, with a PPV of 18%
with contrast including delayed images of the and NPV of 100% with referent standard being
collecting system and ureter should be histopathology from biopsy or radical nephroureterectomy
performed. (Strong Recommendation; Evidence (RNU). An important caveat is that renal cell carcinoma
Level: Grade B) accounted for two-thirds of the cases in this series and
that the study was not structured as a head-to-head
Cystoscopy is an essential component of the evaluation
comparison of US and CT.13 Recognizing these
for patients with suspected UTUC due to the risk of
limitations, the Panel cannot recommend the routine use
concurrent lower tract urothelial cancer in this population.
of renal sonography for evaluating patients with
If there are no contraindications to its use, clinicians suspected UTUC though recognizes there may be clinical
should perform a multiphase computed tomography (CT) utility in the narrow indications where contrast-based CT
scan with excretory phase imaging of the urothelium. A and MRI studies cannot be performed.
systematic review by Janisch et al. highlighted that CT
2. Clinicians should evaluate patients with
urography was associated with a pooled sensitivity of
suspected UTUC with diagnostic ureteroscopy
92% (95% CI: 85% to 96%), pooled specificity of 95%
and biopsy of any identified lesion and cytologic
(95% CI: 88% to 98%), and a summary area under the
washing from the upper tract system being
ROC curve of 0.97 (95% CI: 0.96 to 0.98)11 using
inspected. (Strong Recommendation; Evidence
histopathology or a negative clinical follow-up as referent
Level: Grade C)
standard. Two additional studies published after the
systematic review reported results consistent with this After initial concerns of UTUC are discovered on imaging,
review.12, 13 endoscopy by antegrade or retrograde approach with
tissue sampling and cytologic washing should be
In patients with contraindications to contrast-enhanced
performed when diagnostic and prognostic details are
CT such as chronic kidney disease (CKD) or untreatable
needed. When performed, this diagnostic procedure
allergy to iodinated contrast medium, clinicians may utilize
should be performed as a standardized endoscopic
magnetic resonance (MR) urography. In a study of 88
examination including elements pertinent to clinical
patients, Takahashi et al. found MR urography was
decision-making. At ureteroscopic evaluation, clinicians
associated with a per-patient sensitivity of 63% to 74%
should document key descriptive features of UTUC
and specificity of 96% to 97% for diagnoses of UTUC.14
including tumor size, number, location, focality, and
For patients with contraindications to multiphasic CT and appearance. These factors may guide further diagnostic
MR urography, clinicians may utilize retrograde testing and inform therapeutic interventions as well as
pyelography in conjunction with non-contrast axial provide points of comparison for subsequent
imaging to assess the upper urinary tracts. Renal ureteroscopic surveillance. An example checklist for
ultrasound (US) may also have utility in providing standardized endoscopic diagnostic examination is
additional diagnostic assessment. In a study of 151 provided in Table 3. The Panel recognizes and
imaged urinary tracts, retrograde pyelography was emphasizes a distinction between diagnostic and
associated with a per-tract diagnostic sensitivity of 96%, therapeutic endoscopic procedures for UTUC. Diagnostic
specificity of 97%, positive predictive value (PPV) of 87%, procedures are intended as low-impact and typically brief
and negative predictive value (NPV) of 97%15 with interventions to provide clinical information required for
referent standard of histopathology (biopsy or final risk-adapted patient care whereas therapeutic
surgical pathology) and clinical follow-up for 3-5 years. endoscopic procedures are often longer, more technically
While no reports have specifically evaluated the involved operations undertaken with curative intent and
10

greater risk for surgical complications. Under either The Panel recognizes there are rare situations where
circumstance, it is recommended that standardized endoscopic upper tract evaluation may not be necessary,
reporting of findings be documented. Diagnostic and when other diagnostic means clearly confirm the
therapeutic procedures may overlap under circumstances diagnosis of UTUC and thus histologic tissue confirmation
where discovered tumors are small and can be easily and is not clinically required. Such scenarios may include
completely treated at the time of endoscopy. It is further those patients with high-grade (HG) selective cytology or
recognized that endoscopic procedures carry risks other source of tissue diagnosis, and clear and convincing
including perforation and tumor seeding, inside and radiographic findings of upper tract urothelial-based
outside the urinary tract,that may complicate future tumor(s) such as patients with an obvious enhancing,
management. Data on the comparative risks of retrograde urothelial based soft-tissue filling defect on contrast-
vs antegrade percutaneous approaches are insufficient to enhanced imaging with urography. Such situations may
address the concern regarding potential risk of tumor be particularly relevant in patients with a history of HG
seeding with percutaneous techniques. urothelial cancer. Other clinically justifiable scenarios for
omitting diagnostic endoscopic evaluation may occur
Different techniques exist for endoscopic approach when findings would not influence decision-making, such
including retrograde ureteroscopy versus antegrade as patients with severe co-morbidities who are ineligible
percutaneous nephroscopy and/or ureteroscopy. Both for intervention or request expectant management. In
approaches allow visualization of suspected lesions, and such cases it is recommended that documentation of
a variety of biopsy techniques can subsequently be clinical rationale is provided.
employed which can successfully yield tissue adequate
for diagnosis. Factors such as tumor location, Urine cytology can be helpful in identifying carcinoma in
configuration, size, and patient factors (e.g., prior the upper tracts. Adjunctive cytologic barbotage washing
cystectomy) may influence the chosen approach or with saline obtained from selective ipsilateral collection
technique. Data on comparative effectiveness across all prior to use of any contrast is preferred to a voided urinary
clinical situations are lacking. specimen due to improved cellular yield, to avoid potential
contamination in case of concomitant bladder and/or
Six studies evaluated the diagnostic accuracy of prostatic urethral disease as well as theoretical dilution of
endoscopic (ureteroscopic) biopsy for UTUC, compared the specimen from a normal contralateral unit, all of which
against a reference standard of surgical pathology (e.g., further reduce sensitivity.22 Urine cytology classification
following nephroureterectomy [NU]) or surgical pathology has been standardized under The Paris System, which
plus clinical follow-up.16-21 One study (n=93 patients with prioritizes the identification of HG cells while minimizing
118 biopsies) found ureteroscopic biopsy with forceps the ambiguity of non-HG findings. By this convention,
was associated with diagnostic sensitivity of 83% and urine cytology is reported according to seven categories:
specificity of 100%.18 Another study (n=45) reported nondiagnostic, negative for HG urothelial carcinoma
fluoroscopically guided retrograde brush biopsy was (NHGUC), atypical urothelial cells (AUC), suspicious for
associated with diagnostic sensitivity of 91% and HG urothelial carcinoma (SHGUC), HGUC, low-grade
specificity of 88% for UTUC.21 Additional details of biopsy (LG) urothelial neoplasm (LGUN), and other
and cytology sampling accuracy are provided in Appendix malignancies.23 Adoption of The Paris System began in
I. Although the sensitivity and specificity of biopsy by 2016, taking time to become more widely accepted, and
forceps or loop for yielding a diagnosis of UTUC may be thus may impact interpretation of studies with data
higher than brush biopsy and/or fine-needle aspiration obtained prior to use of this standard.
(FNA) and thus be preferred, patient and tumor
characteristics will likely dictate the optimal biopsy Urine fluorescence in situ hybridization (FISH) testing
technique. Mucosal abnormalities may be difficult to may also be helpful in the diagnosis of UTUC. One
biopsy effectively and thus attempted tissue confirmation previously described systematic review24 including 14
may be facilitated with the use of brush biopsies or studies (N=2,031) found that FISH was associated with
percutaneous image-guided biopsy. high diagnostic accuracy for identifying UTUC with a
pooled sensitivity of 84% (95% CI: 74% to 90%; range:
52% to 100%) and a pooled specificity of 90% (95% CI:
11

85% to 93%; range: 33% to 96%). The pooled positive 3. In patients who have concomitant lower tract
and negative likelihood ratios were 7.96 (95% CI: 5.87 to tumors (bladder/urethra) discovered at the time of
10.81) and 0.18 (95% CI: 0.11 to 0.29), respectively. ureteroscopy, the lower tract tumors should be
Based on the head-to-head comparisons in the review, managed in the same setting as ureteroscopy.
sensitivity of FISH was higher than for voided urine (Expert Opinion)
cytology, with similar specificity. However, use was not
evaluated for selective, instrument-obtained samples A common clinical scenario when managing patients with
from the suspected upper tract. Analogous to cytology, UTUC, the finding of urothelial tumors in the lower tract
selective collection from the suspected renal and/or (bladder or urethra) warrants appropriate independent
ureteral unit likely improves performance characteristics. guideline-directed management in the same surgical
Given the high sensitivity and low specificity of FISH setting by biopsy, resection or ablation as clinically
compared to voided cytology, the Panel acknowledges indicated. This feature of UTUC has been described
the yet uncertain role of FISH and suggests such testing clinically and further investigated through genomic
may be considered adjunctively to adjudicate atypical or studies, which show clonal similarity between upper and
suspicious cytology results.
Table 3: Standardized Upper Tract Endoscopy Suggested Reporting Elements

Elements Reporting
Approach □ Antegrade □ Retrograde
Access Details:
Bladder Lesions □ No □ Yes
If yes, Details:
Ureteral Lesions □ No □ Yes
If Yes, Location: □ Lower □ Mid □ Upper
Appearance □ Papillary □ Sessile □ Flat □ Other:
Focality □ Unifocal □ Multifocal
Largest Size _______mm Visual Reference:
Obstruction □ No □ Yes
Biopsied □ No □ Yes
If yes, Details:
Cytology □ No □ Yes
Renal Pelvis / Calyceal □ No □ Yes
Lesions
If Yes, Location: □ Upper Calyx □ Mid Calyx □ Lower Calyx □ Pelvis
Appearance □ Papillary □ Sessile □ Flat □ Other:
Focality □ Unifocal □ Multifocal
Largest Size _______mm Visual Reference:
Obstruction □ No □ Yes
Biopsied □ No □ Yes
If yes, Details:
Cytology □ No □ Yes
Ancillary Tests Bladder Cytology □ No □ Yes
Upper Tract Washing □ No □ Yes
Uretero-Pyelogram □ No □ Yes Details:
Cystogram □ No □ Yes Details:
Other:
Visualization Quality □ Good □ Limited □ Poor
Comments Observations:
12

lower tract tumors, suggesting either downstream or 5. In cases where ureteroscopy cannot be safely
upstream tumor implantation as a potential mechanism. performed or is not possible, an attempt at
The pathology findings from bladder tumor sampling often selective upper tract washing or barbotage for
reflects that of upper tract tumors, though not reliably cytology may be made and pyeloureterography
enough to be used as rationale for avoiding separate performed in cases where good quality imaging
upper tract endoscopy and biopsy when feasible.2, 25 such as CT or MR urography cannot be obtained.
(Conditional Recommendation; Evidence Level:
Consensus on prioritization of procedure sequencing Grade C)
(managing bladder before or after same-setting
ureteroscopy) is lacking and heavily scenario-dependent. Findings from selective cytology and retrograde
Rationale for managing the bladder first include pyelography may provide useful, objective and sufficient
optimizing visualization within the bladder, avoiding back- information for risk stratification when endoscopic
pressure or back-washing into the upper tract in the case examination of the involved upper tract is not possible. 22
of post-ureteroscopy stenting, and permitting final Example scenarios may include washings taken at the
confirmation of bladder hemostasis. Addressing the upper time of percutaneous nephrostomy tube placement or
tract first may be preferred in cases of bulky bladder tumor during attempted retrograde ureteroscopy that is
involvement where complete resection is not possible or abandoned for safety concerns. Cytologic sampling from
bulky upper tract disease in which risk assessment is the the upper urinary tract, either by barbotage (irrigation and
priority. Seeding of tumors from bladder to upper tract or aspiration) or by irrigation with passive collection
from upper tract to the lower tract have been raised as (washings) can be used to improve cellular yield for
legitimate concerns which some have addressed by cytologic evaluation and best performed prior to
advocating use of ureteral access sheaths in such pyelography to avoid artifactual cellular changes from
circumstances, yet the benefits of this approach require contrast solutions. The Panel recognizes that this
further prospective study. approach is supported by evidence associated with
Statement 2 above and felt that guidance on this scenario
4. In cases of existing ureteral strictures or difficult was warranted as a Conditional Recommendation to
access to the upper tract, clinicians should describe means for risk-directed patient care in the setting
minimize risk of ureteral injury by using gentle of limited data from endoscopy, biopsy, and imaging.
dilation techniques such as temporary stenting
(pre-stenting) and limit use of aggressive dilation 6. At the time of ureteroscopy for suspected UTUC,
access techniques such as ureteral access clinicians should not perform ureteroscopic
sheaths. (Expert Opinion) inspection of a radiographically and clinically
normal contralateral upper tract. (Expert Opinion)
Perforation or disruption of the urothelium in patients with
UTUC can risk tumor seeding outside the urinary tract. Indications for ureteroscopy or percutaneous endoscopy
Precautionary measures in cases of difficult ureteral of the upper urinary tract include such findings as
access such as avoiding dilation or placing a stent without lateralizing hematuria, suspicious selective cytology, and
performing ureteroscopy and then returning one-two radiographic presence of a mass or urothelial thickening.
weeks later to repeat the procedure (pre-stenting) can Endoscopic procedures have risks for patient injury and
decrease the risk of iatrogenic injury and provide the potential for tumor seeding in the presence of
opportunity for a safer and more successful procedure. urothelial cancer. Performing upper tract endoscopy in the
Recognized perforation or injury events should be setting of a completely normal contralateral upper urinary
documented with immediate cessation of the procedure tract without clinical indication or as a “screening”
as soon as safely possible with additional steps to limit procedure is unnecessary, placing patients at undue risk
sequelae (e.g., stenting, bladder decompression with and should not be performed.
urethral catheter drainage to limit reflux, nephrostomy
tube placement in cases of a completely obstructive
ureteral tumor and evidence of contrast extravasation).
13

7. For patients with suspected/ diagnosed UTUC, contralateral upper tract involvement, which is an
clinicians should obtain a personal and family important potential clinical consideration when developing
history to identify known hereditary risk factors a treatment plan. The Panel notes that developing data
for familial diseases associated with Lynch on systemic therapies focused on targeting LS-
Syndrome (LS) (colorectal, ovarian, endometrial, associated cancers are expected to impact future
gastric, biliary, small bowel, pancreatic, prostate, therapeutic options for these patients, further reinforcing
skin and brain cancer) for which referral for the overlap between genetic risk factors and need for
genetic counseling should be offered. (Expert alignment with clinical guidelines for preventative and
Opinion) therapeutic management of UTUC in patients with LS.
The significant role of hereditary risk factors in numerous For UTUC patients with familial risk factors, clinical
malignancies is well recognized and a topic that care suspicion, or interest in further testing for hereditary
providers must be familiar and comfortable discussing syndromes, clinicians can perform initial screening tests
with patients. (described below), and should offer referral for genetic
counseling and, if indicated, genetic testing.
LS is common among patients with UTUC, accounting for
an estimated 7-20% of U.S. cases. However, LS is 8. Universal histologic testing of UTUC with
frequently unrecognized as a risk factor in this setting and additional studies, such as immunohistochemical
warrants specific attention during clinical assessment. (IHC) or microsatellite instability (MSI), should be
Routine evaluation should include a detailed personal and performed to identify patients with high
family history to ask about specific LS associated cancers probability of Lynch-related cancers whom
to clinically identify at-risk patients and their family clinicians should refer for genetic counseling and
members. germline testing. (Strong Recommendation;
LS is a familial, autosomal-dominant multi-organ cancer
syndrome estimated to affect roughly 1 in 280 individuals Clinical screening criteria including standard Amsterdam
in the U.S.26 It is widely and strongly recommended (e.g., II criteria and Bethesda guidelines (Table 4) are useful in
ASCO, National Comprehensive Cancer Network providing background context yet are unreliable, difficult
[NCCN], Centers for Disease Control and Prevention to implement, and fail to identify a significant proportion of
[CDC]) that patients with LS undergo routine screening patients with LS or sufficiently exclude patients from
due to increased life-long risk for developing associated screening.28 Routine tissue testing provides a more
malignancies, often occurring before 50 years of age, sensitive, first-line means to identify LS-associated
though not exclusively.27 The most commonly features in tumor samples, thus providing clinically
encountered are colorectal (20-80%), urothelial (1-18%), significant information for patient counseling and
and gastric cancers (1-13%) in both men and women; and management as well as screening for family members.
endometrial (15-60%) and ovarian cancer (1-38%) in IHC testing for example, which is widely available, can
women. Practice guidelines by several organizations preliminarily identify the altered proteins associated with
(e.g., US Multi-Society Task Force on Colorectal Cancer LS, and thus help to identify patients who may have the
[MSTF], ASCO, European Society of Medical Oncology syndrome, who then require confirmation with further
[ESMO], NCCN, American College of Gastroenterology genetic (germline) testing.
[ACG], American College of Obstetrics and Gynecology
[ACOG]) recommend routine clinical screening including LS results from an inherited germline mutation in a group
the use of standardized genomic questionnaires for all of DNA damage response genes responsible for biologic
patients with related gastrointestinal (colon, gastric) and mechanisms of mismatch repair (MMR), specifically
gynecologic (endometrial, ovarian) cancers. MLH1, MSH2, MSH6, PMS2, or EPCAM.28 Alterations
affecting the normal function of these genes results in an
Competing LS-associated cancers or related suspicious accumulation of DNA errors and increases the potential
findings can pose potential clinical challenges requiring for cancer development. Tumor tissue testing by
involvement and coordination of multi-disciplinary care. In histologic studies such as IHC can indicate loss of these
UTUC specifically, LS may increase the possibility of specific MMR proteins or evaluate for MSI status as a
14

standard means to assess for the possibility of LS- cancers (CRC) due to the high rate (3%) of LS and the
association. Suspicious findings with these tests require indication of significant, cost-effective clinical benefits for
further confirmatory testing, for which patients should be patients and family members.28 Of the strategies
referred to a specialist for genetic counseling. investigated and endorsed, reflex IHC studies for MMR
and MSI testing were highlighted for their high sensitivity
Recommendations and guidelines in other LS-related and specificity. The Panel acknowledges the EGAPP
cancers strongly endorse universal MMR and MSI testing. report did not evaluate or address testing in UTUC but
A detailed analysis by the Evaluation of Genomic similarly endorses an analogous strategy in that the Panel
Applications in Practice and Prevention (EGAPP) recommends genetic testing to all patients with UTUC due
Working Group from the CDC reported sufficiently strong to the higher identified prevalence of LS association in
evidence to recommend genetic testing routinely be UTUC relative to CRC.
offered to all patients with newly diagnosed colorectal
Table 4: Clinical Screening Criteria for LS (also referred to as hereditary non-polyposis colorectal cancer
[HNPCC])
Amsterdam II Three relatives with any LS-associated cancer (colorectal cancer, cancer of the endometrium, small
bowel, UTUC)
Two successive generations should be affected
One should be a first-degree relative of the other two
One should be diagnosed before age 50
Revised Bethesda Tumors in families that meet Amsterdam II criteria

Guidelines
Colorectal cancer diagnosed in a patient who is less than 50 years of age
Presence of synchronous, metachronous colorectal, or other LS-associated tumors, regardless of age
Colorectal cancer with MSI-high testing diagnosed in a patient who is less than 60 years of age
Colorectal cancer diagnosed in one or more first-degree relatives with an LS-related tumor, with one
of the cancers being diagnosed under age 50 years
Colorectal cancer diagnosed in two or more first- or second-degree relatives with LS-related tumors,
regardless of age
Adapted from Revised Bethesda Guidelines for Hereditary Nonpolyposis Colorectal Cancer (Lynch Syndrome) and Microsatellite
Instability and New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International
Collaborative group on HNPCC.33, 34
The NCCN Guideline Genetic/Familial High-Risk recommendations are founded on findings from a large
Assessment: Colorectal version 1.2022 endorses data set of over 15,000 LS-related cancers (including 551
universal MMR testing of all CRC and endometrial urothelial cancers) screened with MSI, MMR and germline
cancers and recommends considering universal testing of genomic testing which identified LS-association in over
other LS-related malignancies regardless of the age of 16% of cases of patients with MSI-high signatures and
diagnosis including urothelial cancers. These specifically 37.5% in urothelial cancer cases.27
15

From the guideline systematic review, four retrospective (invasion, obstruction, and lymphadenopathy)
cohort studies were identified that evaluated factors features to facilitate clinical staging and risk
associated with LS in patients diagnosed with UTUC.29 assessment. (Strong Recommendation; Evidence
Although the patient numbers in these series were Level: Grade B)
modest, limiting the analyses, the use of MMR and MSI
testing was significantly associated with identification of Tumor features identifiable by endoscopic and radiologic
LS patients within studied cohorts when used adjunctively assessment are strongly associated with disease risk
with standard clinical screening criteria. One study and, therefore, necessary to properly inform risk
evaluated a universal molecular screening strategy stratification, treatment decision-making and assessment
against a genetic testing standard. Patients who screened of treatment response.35-41 Standard reporting of
positive by standard clinical criteria (Amsterdam II), had endoscopic findings is, therefore, critical to document and
loss of one or more MMR proteins, or had high MSI, were communicate objective clinical findings. At the time of
considered to have “potential LS,” and were referred for examination by antegrade or retrograde approach,
germline testing. Of 115 patients screened, 13.9% had clinicians should document key features including the
potential LS: 7.0% met Amsterdam II criteria; 11.3% had following:
loss of at least one MMR protein; and 5.7% had high MSI.
 Sites of involvement (ureteral segment, renal
Of the 16 patients with potential LS, 9 completed germline
pelvis, calyceal sites and lower tract)
testing, with LS confirmed in 6 patients (5.2% of the total
 Number of tumors or presence of multifocality
115 patients screened). These data are comparable with
described results from large cohort screening studies in  Tumor appearance (sessile, papillary,
LS malignancies.27 flat/villous)
It must be acknowledged that MMR or MSI studies are It is also recommended that documentation include an
screening tests and are neither genetic tests nor a gold estimate of the largest tumor size, if possible, by using a
standard for identifying LS. As such, these tests may miss reference standard such as the scope tip, basket, laser
10% or more with the disease.30 Germline genetic testing, fiber, biopsy forceps, or brush. Quality of visualization can
also considered a molecular study, is a more definitive impact the accuracy of endoscopic inspection (e.g.,
means of diagnosis requiring specific counseling and bleeding, difficulty in access, tumor location, artifacts from
justified if available – yet may also fail to identify familial instrumentation) and should be documented in
cases of Lynch-like syndromes caused by epigenetic endoscopic reports.
phenomena. Universal molecular testing serves a key role
along with clinical awareness when evaluating UTUC Radiographic characterization of tumor features is also
patients providing the opportunity for discussion of informative for clinical staging. As noted, retrograde
genetic risk factors with patients and sufficient indication urography should be performed concomitantly with upper
for appropriate genetic counseling referral for any patient tract endoscopic assessment and documentation of filling
with UTUC. The Panel notes that identifying the presence defects or evidence of urinary tract obstruction should be
of LS-associated and MSI-high cancers also has clinical provided. Reporting from contrast-enhanced cross-
implications related to therapeutic treatment options, sectional imaging should include details of tumor
including identified sensitivity of urothelial cancers with characteristics that suggest invasive features, obstruction
mutations in DNA damage repair genes to systemic of the urinary tract, and locoregional progression such as
agents such as immune checkpoint inhibitors and cis- suspicious lymphadenopathy, and/or presence of
platinum-based chemotherapy.31, 32 metastatic disease.
10. Following standardized assessment,

RISK STRATIFICATION clinicians should risk-stratify patients as
“low-” or “high” risk for invasive disease (pT2
9. At the time of identified UTUC, clinicians should
or greater) based on obtained endoscopic,
perform a standardized assessment documenting
cytologic, pathologic, and radiographic
clinically meaningful endoscopic (focality,
findings. Further stratification into favorable
location, appearance, size) and radiographic
16

and unfavorable risk groups should then be There are limited data on the independent value of FISH
based on standard identified features (Table testing to identify advanced stage disease, and its routine
5). (Strong Recommendation; Evidence Level: use for this purpose cannot be supported now. The
Grade B) association of FISH with the presence of a HG tumor is
recognized and may have value as an adjunct test in
Determining cancer-associated risk is critical to guide some scenarios where tissue sampling is challenging and
risk-adapted treatment selection and patient counseling. cytology is indeterminate. Two studies (N=244) reported
Tumor characteristics determined from the standardized on the diagnostic accuracy of FISH for identifying HS
process of clinical assessment described in this guideline disease in confirmed UTUC.44, 45 The studies used the
allows categorization of tumors into high- and LR groups. reference standard of histologic confirmation on final
The association of HG cancer (HG biopsy or cytology) surgical pathology report from NU or distal ureterectomy
with disease progression risk and pathologic stage T2 or and defined HS as ≥pT2. Sensitivity was from 72% to 83%
greater disease defines the category of HR whereas LG and specificity was 38% to 47%, for PPV of 58% to 60%
cancer (LG biopsy and normal cytology) defines LR and NPV of 63% to 67%. One of the studies found that
disease. FISH results were not significantly associated with
increased likelihood of HS disease (p=0.12).45
It is recognized that heterogeneity within these two
categories exists, warranting further stratification by
IMAGING
distinct clinically identifiable features. The factors below
highlight these additional findings to aid sub-stratification CT
within the HR and LR categories and to guide risk- The sensitivity and specificity of specific CT findings for
adapted management strategies. An accounting of the identifying HG disease varies (Appendix II); the CT finding
data supporting these additional features is also included with the best combination of sensitivity and specificity was
in Appendix tables II and III. presence of heterogeneous texture (versus
homogeneous; sensitivity: 70% and specificity: 100%)
BIOPSY with a PPV of 100% and a NPV of 28%. 46, 47 However,
The association of HG tumor on ureteroscopic biopsy with these predictive values should be interpreted with caution
high-stage (HS) disease (≥pT2) on final pathology (13 due to a low proportion of patients with LG UTUC in the
studies, N=1,197) has a PPV of 60% (95% CI: 54% to study cohort. The presence of ipsilateral
66%; range: 33% to 85%; I2 = 57.0%) and a pooled NPV hydroureteronephrosis demonstrates limited diagnostic
of 77% (95% CI: 73% to 82%; range: 67% to 100%; I2 = accuracy for the findings of HG UTUC, with a sensitivity
19.8%), indicating room for further refinement along the of 40% to 43% and specificity of 60% to 66%, which was
spectrum of favorable to unfavorable within the HR and further supported by a study by Ng et al. in which
LR groups.42 Sub-stratification features have been hydronephrosis on CT was not significantly associated
identified and reported in publications and nomogram with HG UTUC (p=0.49).47
formats and are recognized by the guideline Panel as
being useful for further risk refinement. Similarly, the sensitivity and specificity of specific CT
findings for identifying HS UTUC, which is defined as
CYTOLOGY >pT2, is variable. Five studies reported on the diagnostic
Selective ipsilateral upper tract cytology provides accuracy of CT for identifying HS disease in confirmed
supplemental histologic data to tumor biopsies and the UTUC.46-50 Heterogenous texture on enhanced and even
finding of HG cytology in the setting of LG biopsy findings unenhanced CT imaging has been associated with
indicates the likely presence of higher-risk features (e.g., invasive disease.51 In a study of 48 patients with UTUC,
HG tumor) missed on biopsy sampling. Obtaining the presence of heterogeneous (versus homogenous)
selective cytology after tumor biopsy can improve the texture was associated with the best combination of
yield of cells for cytologic analysis.43 sensitivity (91%) and specificity (58%) for advanced
stage, with a PPV of 66% and NPV of 88%. In this series,
FISH identification of hydronephrosis on CT was associated
with a 4-fold increase in the risk of HS UTUC (hazard
17

ration [HR]: 4.0; 95% CI: 1.4 to 11.5, p=0.01). The role and warrant either prospective evaluation or, at a
sensitivity of multidetector CT identifying HS disease minimum, further testing under controlled clinical
(≥pT3) ranges from 0.28 – 0.75, while the specificity circumstances such as quality improvement studies. MRI
ranges from 0.84-1.00.46, 48, 50 Specific features that have can provide some soft tissue details in patients who
been proposed to predict HS UTUC include the presence cannot receive contrast, offering some advantages in
of local invasion on CT and the presence of pathologically such patients by identifying features of fat invasion with
enlarged lymph nodes, both of which are associated with diffusion weighted imaging associated with very
a relatively modest sensitivity of 0.49 and 0.22, advanced, T3 disease.52 However, MRI can falsely over-
respectively, with a higher specificity (0.85, and 0.98, estimate tumor stage due to surrounding tissue effects
respectively).49 that may mimic tumor invasion such that establishing
cutoffs for diffusion weighted imaging have not been well
OTHER IMAGING established.53 At present, the Panel recommends such
Retrograde pyelograms provide a roadmap for evaluation studies only as supplements to current standards of care.
and possibly planning kidney-preserving strategies and
should be considered at initial evaluation with images
retained in the patient record. Modalities such as
endoluminal US do not yet have a well-defined clinical
Table 5: Presurgical Clinical Risk Categories

Risk Stratification
Feature Low-risk High-risk
Biopsy Grade Low-Grade High-Grade
Sub-stratification Favorable Unfavorable Favorable Unfavorable
Cytology* Negative cytology No HGUC Any Cytology HGUC
Radiography No invasion No invasion No Invasion Invasion
No obstruction Obstruction No obstruction Obstruction
Normal nodes Normal nodes Normal nodes Suspicious nodes
Appearance Unifocal Multifocal Unifocal Multifocal
Papillary Papillary Papillary Sessile or Flat
Lower Tract No involvement Involvement No involvement Involvement
Involvement**
Therapy
Ablative Treatments Preferred May be offered Rare, selected cases Palliation
Systemic Therapy Not recommended Not Neoadjuvant or Neoadjuvant or
recommended adjuvant adjuvant
* Per the Paris system criteria for interpretation of urinary cytology which recognizes 7 categories for cytology reporting: nondiagnostic, negative for HG
urothelial carcinoma (NHGUC), atypical urothelial cells (AUC), suspicious for HG urothelial carcinoma (SHGUC), HG urothelial carcinoma (HGUC), LG
urothelial neoplasm (LGUN), and other malignancies.
** Concomitant or prior history of lower tract involvement.
18

function due to loss of a renal unit. A median decline in

TUMOR APPEARANCE, GROWTH renal function after NU up to 32% has been reported
CHARACTERISTICS AND LOWER TRACT which can induce or exacerbate a state of CKD, affect a
INVOLVEMENT patient’s candidacy to receive adjuvant chemotherapy. 57,
58
Tumor features associated with more aggressive cancer
risk include sessile versus papillary appearance, multi-
Patients with UTUC should, therefore, undergo an
focality, and, relatedly, pan-urothelial disease as
assessment of renal function and, for individuals who are
indicated by history of prior cystectomy, concomitant or
scheduled to undergo NU and especially those who may
metachronous lower tract urothelial cancer or
require perioperative systemic treatment, an estimation of
contralateral UTUC diagnosis.54, 55 Each of these features
post-operative renal function should be made.
are considered unfavorable if present. Recognizing no
Recommended tests include serum creatinine to
single finding can reliably provide adequate staging or
calculate an eGFR and, at the clinician’s discretion for
risk-stratification in isolation, several groups have tried to
more refined evaluation, split function testing such as with
combine multiple variables to strengthen predictive ability.
differential renal scan or CT volumetric studies.
The Panel acknowledges the debate on issues including
Perioperative nephrology consultation can be considered
overlap in several of these features and aspects of
as well, particularly in patients with pre-existing kidney
additive risk when more than one feature is present,
disease. Attention should be paid in the settings of renal
describing a spectrum of risk, which can be weighted and
atrophy and hydronephrosis, which may alter clinical
considered during shared decision-making and treatment
estimates of resulting post-operative renal function.
election.
Hydronephrosis caused by tumor obstruction may falsely
under-estimate preoperative renal function and alter
OTHER FEATURES
decision-making around the use of neoadjuvant
The Panel recognizes that other features have been
chemotherapy (NAC). Thus, in settings of
identified that may have an association with disease risk
hydronephrosis, renal decompression either by indwelling
(e.g.., tumor size, lymphovascular invasion (LVI)
ureteric stent or a percutaneous nephrostomy tube placed
neutrophil-to-lymphocyte ratio, tp53 or FGFR3 mutation
in an uninvolved renal calyx along with oral fluid hydration
status). However, these variables may not be widely
for 7-14 days before re-checking eGFR will help to
available, easily identified or measured, thereby limiting
establish a more accurate estimation of baseline renal
broad applicability. Specifically, tumor size has a
function. Ureteric stenting is the preferred method of
described association with tumor grade and stage;
drainage given the known risk of tract seeding with
however, measurement in the pre-surgical setting is not
percutaneous nephrostomy tubes in the setting of UTUC
standardized and has not been shown to be independent
as well as quality of life considerations 59 Atrophy of the
of other more easily determined clinically identified
contralateral (unaffected) renal unit may lead to over-
features such as multifocality, invasion and obstruction.
estimates of postoperative renal function in the setting of
Importantly, data supporting tumor measurements from
NU since the kidney with lower differential function will
large retrospective databases have been derived from
remain in situ60, 61 Results of renal function investigations
pathology reports after surgical resection and may not be
can help with patient counseling, strategizing treatment
applicable to pre-operative imaging or endoscopic tumor
sequence, and determination of downstream risks of CKD
size estimates – therefore less clinically useful.56
and potential dialysis. In patients with sufficiently poor
11. Patients with UTUC should be assessed prior to CKD in which NU could precipitate ESRD, a post
surgery for the risk of post-NU CKD or dialysis. operative plan for dialysis in conjunction with nephrology
(Expert Opinion) colleagues should be in place preoperatively including
plans for dialysis access. Referral to nephrology for
Initial decisions regarding operative approach and detailed evaluation and recommendations for
administration of systemic therapy are based on patients’ perioperative management is warranted in such cases.
baseline renal function and their estimated post-operative
estimated glomerular filtration rate (eGFR). Patients In patients with pre-existing CKD or a solitary kidney,
undergoing NU have diminished postoperative renal attempts to preserve renal function can be made, if
19

oncologically feasible and appropriate, with segmental or TREATMENT

endoscopic organ-sparing approaches which
preferentially are associated with improved postoperative 12. Clinicians should provide patients with a
renal function.62-64 Notably, in four studies reporting the description of the short- and long-term risks
impact of SU compared to NU on renal function, three associated with recommended diagnostic and
found SU was associated with improved renal function therapeutic options. This includes the need for
versus NU with differences in eGFR ranging from 14 to 19 endoscopic follow-up, clinically significant
mL/m.65-67 strictures, toxicities associated with surgical
treatment and side effects from neoadjuvant and
As stated in the Renal Mass and Localized Renal Cancer:
adjuvant therapies. (Clinical Principle)
Evaluation, Management, and Follow Up: AUA
Guideline,68, 69 predictive factors for post-operative Providing patients with a detailed description of risks and
development of CKD or progression of pre-existing CKD benefits associated with treatment options is a mandatory
include older age, diabetes mellitus, hypertension, as well requirement of care, and clinicians must be familiar with
as male sex, obesity, tobacco use, larger tumor size, and outcomes in upper tract management. Urothelial
post-operative acute kidney injury.70-76 Patients who recurrences are common in the management of UTUC,
present with eGFR less than 45 mL/ min/1.73m 2 or regardless of approach, and mandate long-term
confirmed proteinuria are at particularly HR from a surveillance for which patients must be prepared –
functional standpoint and should be considered for including the potential need for additional treatments.
nephrology consultation. Patients who are expected to Ablative options can provide local control including
have an eGFR less than 30 mL/ min/1.73m 2 after durable long-term kidney sparing outcomes but incur
intervention will also be at HR long-term, and a additional endoscopic surveillance requirements and
nephrologist should be involved in their care. Identifying associated risks such as stricture and infection.78
modifiable risk factors including diabetes mellitus (DM), Specifically, the use of chemoablative treatment with the
hypertension (HTN) and smoking is essential. Optimizing reverse thermo-hydrogel preparation of mitomycin for
glycemic and blood pressure control, smoking cessation pyelocaliceal instillation for LG tumors carries an FDA
and minimizing risk of acute kidney injury (with avoidance label warning for ureteral obstruction (>44%), bone
of hypotension and nephrotoxic agents such as marrow suppression, and embryo-fetal toxicity.79
intravenous contrast or non-steroidal anti-inflammatory Systemic chemotherapy and immunotherapy treatments
drugs) should reduce the degree of renal dysfunction in also have toxicities requiring specific counseling best
the perioperative period.77 Of note, patients with DM are provided as part of multi-disciplinary care.
at even higher risk for acute kidney injury compared with
those without DM, even among those with normal eGFR Kidney Sparing Management
prior to nephrectomy.70 With significant nephron mass
loss, hyperfiltration can occur resulting in glomerular 13. Tumor ablation should be the initial management
damage, exacerbation of proteinuria and progressive option for patients with LR favorable UTUC.
sclerosis with further decline in GFR. Therefore, repeat (Strong Recommendation; Evidence Level: Grade
assessment of blood pressure, eGFR, and proteinuria B)
should be performed soon after nephrectomy then again
in three to six months to assess for development or LR UTUC is associated with low rates of metastatic
progression of CKD. With any compromise in eGFR or progression and presents an opportunity for kidney
presence of CKD complications, additional regular preservation. Endoscopic management (by retrograde
monitoring of kidney function should be performed and ureteroscopy, antegrade ureteroscopy, or percutaneous
resection) is an established treatment option for urothelial
further management of CKD would be recommended with
referral to nephrology. Careful management of DM and cancer, including those involving the upper tract, and
HTN and avoidance of substantial weight gain may slow should be the first-line treatment for patients with LR
or prevent CKD progression and should be prioritized on favorable UTUC when technically feasible. Developing
RCTs is a challenge in this setting since renal functional
a long-term basis.
loss from NU represents a significant medical risk, leaving
20

a small number of patients at individual centers with should not be used as a substitute for complete
normal renal function who might be considered trial- endoscopic ablation whenever feasible.
eligible. There are 13 observational studies that have
compared endoscopic management with NU showing 14. Tumor ablation may be the initial management
similar cancer-specific survival (CSS) and improved renal option offered to patients with LR unfavorable
functional outcomes for patients treated with endoscopic UTUC and select patients with HR favorable
ablation.62-64, 80-89 As these are retrospective studies, disease who have low-volume tumors or cannot
characteristics of patients selected for endoscopic undergo RNU. (Conditional Recommendation;
management versus those managed with NU are varied Evidence Level: Grade C)
and results must be interpreted in the context of strong
There is no high-quality evidence that specifically
case-selection bias. A study by Grasso et al. (n=162) with
compares outcomes of endoscopic management versus
a mean follow-up just over 3 years reported improved 5-
NU for patients who meet specific criteria for LR
year CSS for patients with LG UTUC who underwent
unfavorable or HR favorable UTUC. Collectively,
ureteroscopic management versus those with any grade
comparable cancer-specific survival and improved renal
UTUC who underwent NU in which 10-year DSS were
functional outcomes are reported for patients undergoing
similar (5-year: 87% versus 64%; 10-year: 81% versus
endoscopic management relative to NU (see discussion
78%).82 Further, studies by Rouprêt et al. (n=97) and
in the Guideline statement 13).62-64, 80-89 Some studies
Shenhar et al. (n=61) reported similar 5-year CSS for
have included in their analyses patients with features of
patients who underwent endoscopic management and
unfavorable LR disease (e.g., multifocal LG tumors). 81, 82,
NU (80% to 81% versus 84% and 89% versus 92%, 90 Further, Grasso et al. included patients with pan-
p=0.96).64, 85
urothelial disease and larger tumors but did note a higher
Regarding renal functional outcomes, two studies 81, 87 rate of disease progression in these patients.82
reported similar renal function following endoscopic
Tumors < 1.5 cm in size may be optimal for endoscopic
management or NU, and three studies reported better
ablation given a lower risk of invasive disease.
renal outcomes following endoscopic management.62-64
Conversely, tumors ≥ 1.5 cm in size are associated with
Four studies reported similar rates of surgical
a > 80% risk of invasive disease, and tumors > 2.5 cm are
complications or reported no statistically significant
associated with a lower disease-specific survival.91
differences.64, 81, 84, 85
Further, hazard ratio analyses of tumor size cutoffs of 1.5
In certain clinical scenarios of LR UTUC, complete and 2 cm have demonstrated significant relationships with
endoscopic ablation may not be feasible. Such instances stage ≥ pT2.92
may be predicated on specific tumor (location and
Endoscopic ablation has been reported in patients with
focality) and patient factors (age, comorbidities, baseline
imperative indications with tumors up to 6.0 cm. Scotland
renal function, procedural risk). Chemoablation (in-situ
et al. described their institutional experience treating
tissue destruction) can be a treatment alternative in these
patients with tumors ≥ 2.0 cm in size and found 5-year
situations. In an open label, single arm, phase III trial in
recurrence-free survival (RFS), progression-free survival
patients with LG tumors measuring between 5 – 15 mm,
(PFS), and CSS rates of 10%, 65%, and 84%. 93
Kleinmann et al. reported that a mitomycin containing
Therefore, larger tumors (≥ 1.5 cm) may be considered
reverse thermal gel yielded a 59% (42 of 71 renal units)
for ablation based on the provider’s experience and
complete response at primary disease evaluation, 1
assessment of the need for kidney sparing surgery.
month following a 6-week course of therapy.79 A
subsequent report from these investigators highlighted For patients with LR unfavorable disease who
that 56% of evaluable complete responders remained demonstrate progression in tumor size, focality, or grade,
disease free at 12 months post-therapy.78 The observed the Panel recommends against further endoscopic-
benefit of mitomycin containing reverse thermal gel in assisted attempts and consideration of definitive
these studies must be balanced against the risk of resection via segmental ureterectomy (SU) or NU. In
possible ureteral stricture. Importantly, chemoablation cases of HR favorable cancers managed endoscopically,
clinicians must recognize the higher risks of disease
21

progression and pivot early to definitive surgical resection cancer detection rate at the time of the second look. 95 A
when necessary. 30-day window on either side of this endpoint (i.e., 30 to
90 days) is justified to allow timely identification of
15. Tumor ablation may be accomplished via a recurrences and may be dictated by aspects such as
retrograde or antegrade percutaneous approach tumor size, visualization, access, treatment efficacy, etc.,
and repeat endoscopic evaluation should be as clinically indicated. Clinicians may wish to take a
performed within three months. (Expert Opinion) conservative approach with shorter interval endoscopic
diagnostic and therapeutic endoscopic procedures for
Various approaches and techniques may be employed to
more challenging cases, particularly when incomplete
successfully treat UTUC by ablation. Retrograde
treatment is a possibility. Repeat endoscopic assessment
approaches including ureteroscopy with pyeloscopy is
should occur within three-month intervals until no
commonplace, while percutaneous techniques including
evidence of upper tract disease is identified.
antegrade pyeloscopy or ureteroscopy with ablation is
typically reserved for larger tumors, those that are difficult 16. Following ablation of UTUC tumors and after
to access in a retrograde fashion, or in patients who have confirming there is no perforation of the bladder
undergone prior radical cystectomy or urinary diversion. or upper tract, clinicians may instill adjuvant
pelvicalyceal chemotherapy (Conditional
The energy source employed for ablation may vary based
Recommendation; Evidence Level: Grade C) or
on availability of instrumentation and tumor
intravesical chemotherapy (Expert Opinion) to
characteristics. Thulium laser, holmium laser,
decrease the risk of urothelial cancer recurrence.
Neodymium (Nd:YAG), and electrocautery devices (e.g.,
Bugbee) may all be deployed through an endoscope. There is ample evidence supporting the use of an
Additionally, chemoablation may be employed either immediate instillation of intravesical chemotherapy at the
through retrograde ureteral catheter instillation or time of transurethral resection of a bladder tumor for
percutaneous access with fluoroscopic imaging guidance. urothelial carcinoma for the purpose of reducing the rate
of intravesical tumor recurrence.96, 97 The principle of an
Optional use of a ureteral access sheath during the time
immediate instillation of intravesical or pyelocaliceal
of ureteroscopic ablation can provide some advantages
(upper tract) chemotherapy at the time of endoscopic
for endoscopic assisted ablation when safely employed –
tumor ablation for UTUC is undertaken by extrapolation of
allowing for repeated scope passage up and down the
the data supporting this practice in the management of
ureter for sampling and a means of fluid egress from the
urothelial carcinoma of the lower tract. At present, this is
upper tract to avoid excess pelvicalyceal hydrostatic
considered an optional part of routine practice. The
pressure from irrigation solutions. A study by Douglawi et
available reported clinical experience reported in the
al. demonstrated a lower rate of intravesical recurrence in
upper tract is less compelling. A small, prospective, non-
patients who underwent ureteroscopy with an access
randomized single center cohort study by Gallioli et al.,
sheath compared to those without a sheath prior to NU.94
showed a strong trend in improving urothelial recurrence
Prior to placement of any ureteral access sheath, the
free survival (URFS) for patients treated with a single
entire ureter should be directly visualized in order to avoid
upper tract instillation of Mitomycin C after endoscopic
missing any luminal neoplasms, especially in the distal
ablation. Mean URFS was 29 months for the treated
ureter.
group compared to 19 months in patients who did not
Repeat endoscopic evaluation should take place within receive treatment (log-rank p = 0.067).98 Though a small
three months of the initial treatment due to the proclivity study including only 51 patients, there were controls for
of UTUC to recur and for residual disease to remain after several potential confounding variables and low ROB was
the first ablation. Optimal timing of follow-up endoscopic identified. A larger study (n=73) by Cutress et al. did not
evaluation has not been well established noting that control for confounding variables and failed to identify a
several factors may impact the indication and decision for difference in RFS with adjuvant intraluminal
short interval follow-up such as aspects of visualization. A chemotherapy.99 In the Gallioli study, the majority of
study of 41 patients who underwent a second look recurrences were observed in the bladder.98 More recent
ureteroscopy within 60 days of ablation showed a 51.2% work has explored the role of an adjuvant dose of upper
22

tract mitomycin gel following endoscopic ablation with a of UTCIS detection (voided cytology, selective, cytology,
report of 63% ipsilateral disease-free rate at 6.8 months ureteroscopic visualization, biopsy), and inconsistent
following instillation, albeit with a 19% ureteral stenosis measurements of successful treatment. These systematic
rate and no comparator group.100 While acceptable, there reviews report rates of complete response ranging from
are limited direct supporting data for this common practice 41% to 100%. Rates of recurrence, progression, and
in upper tract applications at this time. transition to radical NU likewise vary from 10% to 46%,
0% to 45%, and 45% to 100%, respectively. Further, AEs
T ECHNICAL CONSIDERATIONS are reported in 0% to 92% of patients across studies and
The optimal administration technique is not fully include cystitis, fever, sepsis, renal tuberculosis, ureteral
elucidated. Both ex vivo and in vivo porcine models stricture, and pericarditis.102, 105
suggest higher rates of topical therapy delivery to the
pyelocaliceal system with retrograde administration by Regarding the treatment of UTUC Ta/T1 disease,
ureteral catheter.101-104 However, the Panel considers Foerster et al. conducted a meta-analysis of 12 non-
each of the following delivery approaches to be randomized observational studies including 212 patients
acceptable: 1) antegrade perfusion by nephrostomy tube, who underwent adjuvant therapy following ablation of
2) retrograde perfusion via ureteral catheter, and 3) Ta/T1 disease.106 Median follow-up was 31 months,
bladder instillation by transurethral catheter with reflux via during which time 39% of patients developed a
a double J ureteral stent. In the third scenario, it is recurrence. Nine studies (with ≥ 10 patients) were
recommended to perform a cystogram and demonstrate included for pooled survival estimates. CSS and overall
adequate reflux of contrast into the pyelocaliceal system. survival (OS) were 94% (95% CI: 86 to 99%), and 71%
Finally, while bacillus Calmette-Guerin (BCG) is the (95% CI: 47 to 90%), respectively. One study included in
mainstay of topical therapies for UTUC, the following the analysis included 22 renal units with Ta/T1 disease
agents have been described: mitomycin c, gemcitabine, and reported progression in 41% of patients.107 Although
docetaxel, epirubicin, adriamycin, thiotepa, and BCG with most studies have used BCG as the therapeutic agent,
interfero105, 106 sub analyses showed no significant differences in
outcomes when other agents were administered.
17. Pelvicalyceal therapy with BCG may be offered to
patients with HR favorable UTUC after complete 18. When tumor ablation is not feasible or evidence
tumor ablation or patients with upper tract of risk group progression is identified in patients
carcinoma in situ (CIS). (Expert Opinion) with LR UTUC, surgical resection of all involved
sites either by RNU or segmental resection of the
Topical therapy may consist of a six-week induction ureter should be offered. (Moderate
course of BCG. Patients should be considered for topical Recommendation; Evidence Level: Grade C)
therapy if imperative indications are present, including
solitary kidney status, bilateral UTUC, or risk of Failure of conservative strategies for kidney preservation
progression to end-stage renal disease. includes the risk of cancer progression, potentially shifting
from curable to an incurable form of UTUC. Clinical
There is a dearth of literature specifically regarding the evidence of a change in tumor growth pattern toward a
treatment of favorable HR UTUC with topical therapy more aggressive subtype should prompt re-assessment
(e.g., BCG). No randomized trials exist to compare of management strategy and consideration for more
outcomes of patients treated with topical therapy versus definitive treatment with extirpative surgical resection.
NU, and retrospective comparisons are limited by small This is especially true for LG cancers, which should not
cohorts.101 However, several small observational studies display evidence of aggressive biology including invasion,
have evaluated the role of BCG as the primary treatment multifocal implantation, HG cytology, or change from non-
of upper tract CIS (UTCIS) and as an adjuvant treatment obstructing to obstructing tumors. Such features should
for Ta/T1 disease. These studies have been summarized prompt a detailed discussion with patients about the
in systematic reviews.102, 105 Regarding the treatment of observed findings, their clinical significance suggesting a
CIS, generalizations of the literature are limited by the shift in disease risk and consideration for change in
lack of a standard definition of UTCIS, variable methods strategy developed through shared decision-making.
23

Data on outcomes comparing endoscopic management (whereby periodic assessments such as imaging or
to extirpative surgery in different risk groups are limited limited endoscopic assessment are performed) or
but provide support for this transparent approach to watchful waiting/expectant management, where
counseling and managing patient expectations. interventions are limited to palliation or awaiting
symptomatic progression – especially in those with very
Thirteen retrospective studies compared endoscopic limited life expectancy. In such cases, patients and family
management versus RNU with baseline differences should be counseled and prepared for disease-related
between treatment cohorts noted.62-64, 80-89 Eight studies events such as bleeding, obstruction, infection, and pain
compared RFS.62-64, 80, 81, 83-86, 89 Of three groups that with options for palliation that may be limited.
reported adjusted risk estimates, one (n=120) found
endoscopic management was associated with an Two studies utilizing large databases compared non-
increased risk of any (local, intravesical, or distant) surgical management versus surgery for UTUC. 109, 110
recurrence (adjusted HR: 3.56; 95% CI: 1.73 to 7.35), 84 Both studies found non-surgical management was
one study found endoscopic management associated associated with worse OS versus surgical treatment
with improved intravesical RFS (adjusted HR: 0.56; 95% though likely reflecting the compromised medical
CI: 0.25 to 1.25),81 and one found endoscopic condition of these patients. Outcomes reported from the
management associated with increased risk of local SEER database (n=8,304; 633 of whom did not undergo
recurrence (adjusted HR: 1.27; p=0.001) but no difference surgery) also observed that non-surgical management
in risk of intravesical RFS (adjusted HR: 0.90; p=0.52). 86 was associated with worse OS (median 1.9 versus 7.8
Nine studies reported outcomes on CSS or all-cause years; p<0.001) and 3-year CSS (74% versus 92%;
mortality (ACM).62, 80-87 Three (n=453, 356, and 170) that p<0.001).110 Another study utilized the National Cancer
controlled for confounding factors found endoscopic Database (n=28,910; 3,157 of whom did not undergo
management was associated with worse CSS surgery) and similarly found non-surgical management to
(propensity-matched HR: 2.1; 95% CI: 1.0 to 4.1; adjusted be associated with worse OS (median 2.0 versus 5.6
HR: 1.18; p=0.12; adjusted HR: 2.00; 95% CI: 0.33 to years; p<0.0001).109
12.50).81, 86, 89 Valid concerns for aspects such as
accuracy of clinical staging, risks of undiagnosed HG Surgical Management
cancers and disease-specific mortality associated with
developing HR disease warrants vigilance in follow-up 20. Clinicians should recommend RNU or SU for
and recognizing clinical signs indicating thresholds for surgically eligible patients with HR UTUC. (Strong
recommending altering care. Recommendation; Evidence Level: Grade B)
19. Clinicians may offer watchful waiting or RNU with complete bladder cuff excision (BCE) and
surveillance alone to select patients with UTUC lymphadenectomy is the standard of care for patients with
with significant comorbidities, competing risks of HR UTUC. Principles of RNU include complete excision
mortality, or at significant risk of End-Stage Renal of ipsilateral upper tract urothelium, including the
Disease (ESRD) with any intervention resulting in intramural portion of the ureter and ureteral orifice with
dialysis. (Expert Opinion) negative margins, and avoidance of urinary spillage, such
as by early low ligation of the ureter, to minimize the risk
Some patients with UTUC have significant comorbid of seeding urothelial cancer outside the urinary tract.
medical conditions that impose serious risks of severe,
treatment-related complications from any form of The RNU specimen should be removed en bloc whenever
intervention. Complication rates following RNU range technically feasible. Open, robotic, and laparoscopic
from 15% to 50% including a 30-day mortality risk of approaches are suitable for RNU so long as the above
1%.108 Such results do not reflect outcomes in non- oncologic and surgical principles are adhered to. The
operative cases where observation and palliative systematic literature review supporting these guidelines
approaches are utilized. Discussion of treatment related demonstrated equivalent oncologic outcomes for open
risks including perioperative mortality may lead to a and minimally invasive (laparoscopic, hand-assisted
shared decision to proceed with active surveillance laparoscopic, robot-assisted laparoscopic) approaches to
RNU.111 Minimally invasive approaches were associated
24

with favorable perioperative outcomes including shorter  Preoperative endoscopic assessment to evaluate
length of stay and fewer complications, and, therefore, are sites of involvement and proximal extent of
favored for most patients when principles of RNU can be disease.
maintained. Case selection criteria are difficult to assess  Preoperative assessment of bladder capacity and
in these analyses such that outcomes across the range of function in cases where more extensive
tumor staging could be a concern and used as rationale reconstruction such as a Boari flap are
for preferentially offering open surgical approaches for anticipated to permit a tension free ureterovesical
large, bulky UTUC with clinical evidence for direct anastomosis or the use of bowel segments.
invasion to adjacent structures.112  Intraoperative pathologic assessment (i.e., frozen
sections) of proximal and distal margins to ensure
Numerous studies demonstrate worse local and
complete resection with negative margins.
metastatic recurrence rates with associated decreased
 Reasonable attempts to avoid of spillage of urine
CSS and OS for patients who did not receive complete
into the surgical field.
BCE.111 BCE can be completed either extravesically or
 Watertight, tension free closure to facilitate
transvesically through a variety of approaches including
functional healing and avoid urine leak (of urine
open, minimally invasive or transurethral endoscopic
potentially contaminated with malignant cells).
techniques. Transurethral endoscopic approaches are
associated with higher recurrence rates in the bladder and
21. For surgically eligible patients with HR and
may limit the ability to utilize post-NU intravesical
unfavorable LR cancers endoscopically
therapies if the bladder is not fully closed.113
confirmed as confined to the lower ureter in a
Ureterectomy including SU with ureteroureterostomy and functional renal unit, distal ureterectomy and
distal ureterectomy with ureteral reimplant are reasonable ureteral reimplantation is the preferred treatment.
alternatives to RNU for well-selected patients. The (Expert Opinion)
literature review demonstrates equivalent oncologic
Distal ureterectomy and reimplantation offers definitive
outcomes for patients undergoing RNU and ureterectomy
curative management for tumors confined to the lower
recognizing the inherent selection differences in the
ureter while preserving kidney function. It is, therefore, the
comparative cohorts.111 The most favorable candidates
treatment of choice for patients with localized cancers in
for distal ureterectomy are patients who have ureteral
this location with an increased risk of disease recurrence
tumors in the lower third of the ureter and a sufficiently
and progression. Other approaches such as endoscopic
mobile bladder with capacity to facilitate reimplantation
assisted tumor ablation are considered alternative options
with or without reconfiguration of the bladder to facilitate
to the gold-standard of extirpative resection and carry risk
a tension-free anastomosis (i.e., Boari flap or psoas hitch
for upper tract tumor recurrence, with reported rates of
maneuver). Patients most suitable for SU have small,
23% to 76%.90 As such, these approaches may yield less
unifocal tumors (typically 1 cm or smaller) tumors isolated
optimal results and require multiple additional
to a short segment of the proximal or mid-ureter requiring
procedures. Of note, CIS limited to the region within the
resection of 2 cm or less of ureteral length to allow for
ureteral orifice. Topical therapies such as BCG along with
primary ureteroureterostomy. Longer sections of ureteral
refluxing ureteral stenting that has been used for in cases
involvement and resection may require more complex
of CIS near the ureterovesical junction or transurethral
reconstruction techniques when kidney sparing is
resection of the transmural portion of the ureter for very
desired. Principles of ureterectomy in select cases
distal tumors, as an extension of bladder resection
include:
procedures, when tumor is limited to the region inside the
 Patient counseling to describe techniques, ureteral orifice and not beyond the bladder wall, thus
potential requirements for urinary reconstruction anatomically managed as bladder cancer.
and associated complications including the
potential impact on postoperative bladder
function.
25

22. When performing NU or distal ureterectomy, the 4,210119), both of which evaluated patients who
entire distal ureter including the intramural underwent NU, the adjusted HRs for cancer-specific
ureteral tunnel and ureteral orifice should be mortality (CSM) with BCE versus no BCE were 0.88 (95%
excised, and the urinary tract should be closed in CI: 0.75 to 1.03)120 and 0.76 (95% CI: 0.66 to 0.88).119 Of
a watertight fashion. (Strong Recommendation, note, this association was also observed in patients with
Evidence Level: Grade B) pT3 (adjusted HR: 0.8; p=0.04), pT4 (adjusted HR: 0.69;
p=0.02), and N1-3 disease (adjusted HR: 0.72;
The management of the ureteral orifice during distal p=0.04).119 Conversely, two studies did not demonstrate
ureterectomy or RNU has been variably described. a statistically significant association between BCE and
Traditionally, this aspect of UTUC surgery has been CSM.115,117 There are insufficient data to date
approached as a formal excision of the bladder cuff documenting associations between BCE and RFS or
surrounding the ureteral orifice and entire ureteral tunnel metastasis-free survival. Limited data demonstrate no
in continuity with the ureter either via a transvesical (e.g., significant difference in harms associated with BCE.
midline cystotomy) or extravesical approach. Depending
on surgeon preference and expertise, this aspect of There are insufficient data to recommend one surgical
surgery can be approached via minimally invasive (e.g., approach to the bladder cuff and ureteral orifice over the
laparoscopic, robotic-assisted laparoscopic) or open other. However, to avoid the risk of incomplete resection
approaches. Others have advocated for a combined of the distal ureter and transmural tunnel, the Panel
endoscopic deep incision surrounding the ureteral orifice recommends that a clinician should perform a formal BCE
or transurethral resection of the ureteral orifice with with watertight closure of the bladder cuff to avoid urinary
extravesical traction to complete the excision (the “pluck” extravasation from the bladder, facilitate more rapid
technique). The resultant hiatus in the bladder in the catheter removal, and permit instillation of intravesical
location of the excised ureteral orifice with or without the adjuvant chemotherapy in the perioperative setting.
bladder cuff can be closed formally in a watertight fashion
in one or more layers; however, delayed closure by 23. In patients undergoing RNU or SU (including
secondary intension in a decompressed bladder without distal ureterectomy) for UTUC, a single dose of
formal bladder closure has also been described. perioperative intravesical chemotherapy should
be administered in eligible patients to reduce the
To date, no RCT has compared the different surgical risk of bladder recurrence. (Strong
techniques for managing the distal ureter and ureteral Recommendation; Evidence Level: Grade A)
orifice during NU or distal ureterectomy for UTUC. This
has been studied in retrospective observational studies Two prospective RCTs have demonstrated that a single
114-120 with sample sizes ranging from 84 to 4,266 (total instillation of intravesical chemotherapy around the time
N=12,125), with low ROB in one study,114 moderate ROB of NU reduces the risk of subsequent intravesical
in five studies,115-117, 119, 120 and high ROB in one study.118 recurrence of urothelial carcinoma. A phase III trial by
Two retrospective studies114, 118 (N=420) demonstrated O’Brien et al. (ODMIT-C Trial) enrolled 284 patients with
that formal BCE is associated with improved 5-year OS no prior history of bladder cancer who were undergoing
versus no BCE (71.5% versus 57.0%; p=0.001).118 In NU for suspected UTUC to either a single post-operative
patients undergoing SU for UTUC of the distal ureter intravesical dose of mitomycin-C (MMC) or standard
(N=84), BCE was independently associated with management at the time of catheter removal.121 On the
improved 5-year OS (92.3% versus 73.7%; adjusted HR: intention-to-treat analysis, 17% of the MMC arm
0.31; 95% CI: 0.08 to 1.18).114 developed a bladder recurrence in the first year compared
to 27% in the standard treatment arm (p=0.055). By
An association between formal BCE and CSS has been treatment as per protocol analysis, 17 of 105 patients
evaluated in seven studies (N=11,478).114-116, 118-120 BCE (16%) in the MMC arm and 31 of 115 patients (27%) in
was associated with improved CSS versus no BCE in all the standard treatment arm developed a recurrence
studies except for two,115, 117 though some differences (p=0.03) with no reported serious AEs. A smaller phase II
were small and/or not statistically significant (Appendix trial by Ito et al. randomized 77 patients to a single
IV). However, in the two largest studies (n=4,266120 and intravesical instillation of pirarubicin or standard care
26

within 48 hours of RNU for UTUC with similar results. 122 pathology, while some may be upgraded or upstaged,
As such, the evidence strongly supports the use of single LND may be considered at time of NU or ureterectomy at
dose of intravesical chemotherapy around the time of the discretion of the clinician according to clinically or
RNU to reduce the risk of subsequent bladder recurrence. radiographically suspicious regional lymphadenopathy or
The exact timing of therapy has varied by study with the other intraoperative findings suggesting more advanced
ODMIT-C trial instilling intravesical chemotherapy at the disease for which nodal staging may be warranted.
time of catheter removal, while other retrospective series
reported instillation during surgery or up to 48 hours 25. For patients with HR UTUC, clinicians should
postoperatively.121-123 perform LND at the time of NU or ureterectomy.
(Strong Recommendation; Evidence Level: Grade
Numerous agents have been used at the time of trans B)
urethral resection of bladder tumor (TURBT) to reduce the
risk of NMIBC recurrence but in the context of UTUC there There have been no RCTs to evaluate the effect of LND
is little data to support one intravesical chemotherapeutic on oncologic outcomes in patients undergoing NU or SU.
over another. However, for many clinicians, the recent Two recent systematic reviews (N=7,516 and N=22,665)
compelling data supporting the use of a single dose of of observational studies compared LND with no LND. 125
intravesical gemcitabine at the time of TURBT for NMIBC Findings of the reviews were consistent, with no
to reduce the rate of intravesical recurrences combined statistically significant differences in oncologic outcomes,
with concerns about potential chemical peritonitis if there including among patients with higher stage tumors. While
is extravesical extravasation of MMC has led many to studies have attempted to adjust for confounders, the
convert their practice to the use of gemcitabine rather ROB in these studies is substantial, especially as it relates
than MMC.123, 124 Nevertheless, in the absence of direct to selection bias: systematic differences in patient
comparisons, ultimately the timing of therapy and choice baseline characteristics, tumor grade, and tumor stage.
of agent can be modified based on the agent availability Moreover, these studies are unable to confirm the extent
and workflow suitable to the clinician. or anatomic boundaries of the LND that was performed.
The Panel conducted a re-analysis of some of the studies

Lymph Node Dissection (LND)
described in the systematic review by Chan et al.126 in
24. For patients with LR UTUC, clinicians may which hazard ratios were all converted so the comparison
perform LND at time of NU or ureterectomy. was in the same direction (LND versus no LND), to pool
(Conditional Recommendation; Evidence Level: data from all studies. In this meta-analysis, LND was
Grade C) associated with better RFS (four studies, HR: 0.58; 95%
CI: 0.40 to 0.83) (Figure 1).
Limited evidence exists to support a beneficial role for
LND at time of NU or ureterectomy among patients with Two additional recent cohort studies127, 128 published
LR UTUC. To date, no RCT has compared LND versus subsequently also compared LND with no dissection. One
no LND with respect to impact on oncologic outcomes. study of patients in the National Cancer Database
(n=5,905) with clinically localized (≤cT4, N0M0) UTUC
Two recent systematic reviews125 of observational studies found LND was significantly associated with improved OS
compared LND versus no LND.126 No statistically (adjusted HR: 0.87; 95% CI: 0.78 to 0.96), but worse 90-
significant differences were noted with regard to LND in day mortality (adjusted OR: 1.53; 95% CI 1.03 to 2.27)
subsequent oncologic outcomes, including among compared to no LND.128 The second study evaluated
patients with higher stage tumors. Therefore, the benefit patients with cN0M0 UTUC (n=7,278) in the SEER
of node dissection among patients with LR UTUC database.127 Compared to no LND, the study found
specifically remains unclear. In one study evaluating performance of a LND was associated with slightly
patients with cN0M0 UTUC (n=7,278) in the SEER improved OS (adjusted HR: 0.87; 95% CI 0.80 to 0.95)
database,127 there was no statistically significant and CSS (adjusted HR: 0.81; 95% CI: 0.73 to 0.95). When
association between lymphadenectomy and OS or CSS patients were stratified according to tumor stage, LND
in patients with T1 and T2 tumors. Given that most was significantly associated with improved OS in patients
patients with LR UTUC have low-stage tumors on final with T3 (adjusted HR: 0.88; 95% CI: 0.78 to 0.99) and T4
27

(adjusted HR: 0.74; 95% CI: 0.59 to 0.94) tumors; while from the renal hilum to at least the inferior
estimates indicated no benefit or were not statistically mesenteric artery.
significant in patients with T1 and T2 tumors. Findings  Tumors in the proximal 2/3 of the ureter: lymph
were similar for CSS, with statistically significant benefits nodes of the ipsilateral great vessel extending
in patients with T3 (adjusted HR: 0.83; 95% CI: 0.73 to from the renal hilum to the aortic bifurcation.
0.98) and T4 (adjusted HR: 0.64; 95% CI: 0.47 to 0.88)  Tumors in the distal 1/3 of the ureter: ipsilateral
tumors and non-statistically significant differences in pelvic LND to include at minimum the obturator
patients with T1 and T2 tumors. and external iliac nodal packets. Internal and
common iliac nodal packets may be removed in
To date, no study has adequately assessed the the appropriate clinical setting. Limited data
distribution of lymph node metastases. As such, the suggest cranial migration of lymph node
appropriate template to yield maximal oncologic metastases to the ipsilateral great vessels such
outcomes and prognostic information remains to be that higher dissection may be considered in the
determined. However, based on anatomic principles, the appropriate clinical setting and per clinician
Panel recommends that the following minimal templates judgement.
may be considered in most settings of clinically non-
metastatic HR disease (cN0M0). Taken in sum, there is sufficient non-randomized
evidence to suggest an oncologic benefit to LND at the
 Tumors in the pyelocaliceal system: lymph
time of NU for patients with “HR” stratification by
nodes of the ipsilateral great vessel extending
guidelines, the Panel recommends LND at the time of NU
or SU for patients with HR UTUC.
F IGURE 1: R EANALYSIS OF R ECURRENCE -F REE S URVIVAL FROM C HAN 2020 S YSTEMATIC R EVIEW
( ALL HAZARD RATIOS CONVERTED TO LND VERSUS NO LND)
Notes:
Only included ureteric arm patients with pT2 disease or above and N0M0
Only included renal pelvic arm patients with pT2 disease or above and N0M0
Only included patients with muscle invasive disease and locoregional recurrence
Only included patients with locally advanced UTUC
28

addition, 62% of eligible treated patients had final

pathologic stage of <ypT1N0/x, an encouraging endpoint
Neoadjuvant/Adjuvant Chemotherapy and given improved long-term outcomes for patients with non-
Immunotherapy muscle invasive cancer following NAC in UTUC in
retrospective series. Accelerated MVAC was tolerated as
26. Clinicians should offer cisplatin-based NAC to expected with 80% of patients completing planned four
patients undergoing RNU or ureterectomy with cycles. No patients progressed prior to surgery, none died
HR UTUC, particularly in those patients whose of chemotherapy- or surgery-related toxicity. At a median
post-operative eGFR is expected to be less than follow-up of 21.1 months, the median relapse-free survival
60 mL/min/1.73m2 or those with other medical for subjects treated with aMVAC and RNU was not
comorbidities that would preclude platinum- reached.
based chemotherapy in the post-operative
setting. (Strong Recommendation; Evidence Renal function outcomes were also evaluated in this trial.
Level: Grade B) Baseline median creatinine clearance was 82 mL/min
(53.7 -170) prior to aMVAC with two patients (6.7%)
Survival outcomes in patients with HR UTUC after RNU having creatinine clearance < 60 mL/min. Following
and LND is poor owing to the aggressive nature of the chemotherapy, 20% had creatinine clearance <60
disease and the resulting compromise to renal function mL/min, all were still surgery eligible. As expected, the
that limits further therapeutic options. Optimizing largest decline in renal function occurred post-RNU with
perioperative systemic treatment to improve outcomes is 69% having calculated creatinine clearance <60 mL/min.
commonly achieved in the neoadjuvant setting when Results from this study have informed the design of
dosing regimens may be better tolerated, allowing more EA8192, a randomized phase II/III trial of neoadjuvant
courses to be completed, and permitting patients to aMVAC +/- durvalumab chemotherapy for four
proceed to appropriate surgical intervention. Several neoadjuvant cycles prior to RNU, currently enrolling.
meta-analyses evaluating NAC for UTUC have identified
evidence for improved pathologic outcomes, CSS, and Coleman et al. presented data from a prospective Phase
OS with this approach.129 II open label trial in a similar population of patients with
HG non-metastatic UTUC planned for RNU, with platinum
Two recently completed NAC trials of cisplatin-based eligible renal function based on calculated glomerular
chemotherapy prior to RNU strongly support this position. filtration rate >55 mL/ min/1.73m 2 by CKD-EPI.134 In this
The designs of these single-arm prospective trials were fully accrued trial, 58 patients enrolled and were treated
extrapolated from data in muscle-invasive bladder cancer with a dosing schedule of split dose cisplatin (35 mg/m 2
that provide high level evidence for neoadjuvant cisplatin on days 1 and 8) with gemcitabine (1,000 mg/m 2 on days
prior to cystectomy compared to surgery alone.130, 131 Both 1 and 8) for 4 planned cycles prior to RNU. The study was
trials used selection criteria that predicted for existing powered at the 90% level to detect a significant reduction
muscle-invasive disease at baseline in over 65% of in pathologic stage <ypT2N0 in ≥60% of patients. This trial
patients.132 In the ECOG 8141 study, four cycles of NAC met its primary endpoint with 63% of patients achieving
with accelerated MVAC (aMVAC, methotrexate, <ypT2N0 status following surgery, including 19% with
vinblastine, adriamycin, and cisplatin with growth factor complete pathologic response (ypT0N0). Median follow-
support every two weeks) were planned.133 Eligible up was 3.1 years and 2- and 5-year PFS was 78% and
patients had HG UTUC of the renal pelvis or ureter, 65%, respectively. The 2- and 5-year OS were 93% and
pathologically confirmed and correlated with cross- 79%, and for both PFS and OS, lower final pathologic
sectional imaging, were without evidence of locoregional stage correlated with better PFS and OS outcomes.
or metastatic disease, and were planned for RNU. In
29/30 aMVAC treated patients, eligibility included ECOG Similar to EA8141, there were no patients with cancer
performance status 0 or 1, and creatinine clearance >50 progression post NAC, which precluded surgery, and no
mL/min. The pathologic complete response rate treatment related deaths. Further, 89% of patients
(ypT0N0/Nx) following RNU in this group was 13.8% received at least 3 cycles of NAC, with 47% completing
(90% CI: 4.9-28.8) and deemed worthy of further study. In all 4. All patients proceeded to surgery. The strongly
28

positive data from these phase II trials, the established A subgroup analysis demonstrated that outcomes for
high-level evidence seen in bladder cancer trials, the patients with lymph node involvement and those treated
consistent findings from pooled meta-analytic data, and with carboplatin chemotherapy were worse than those
the compelling clinical challenges imposed by post-RNU without positive nodes or treated with cisplatin
renal function on cis-platinum eligibility support the chemotherapy.136 As the primary endpoint was powered
standard use of NAC regimens for HR UTUC. Observed based on the intent to treat population, speculation about
results seen with phase II trials also set an important these subgroups, the potential utilization of six versus four
benchmark for any future such studies in this disease. cycles for metastatic N+ disease or the impact of
carboplatin in this setting are hypothesis generating
Alternatives to cisplatin-based chemotherapy (i.e., discussions. Based on these data, carboplatin remains a
immune checkpoint inhibitors, carboplatin, antibody drug reasonable choice for HR cisplatin-ineligible patients
conjugates, targeted FGFR therapies) are not post-RNU if NAC was not given.
recommended in the neoadjuvant setting (prior RNU or
ureterectomy) outside of clinical trials. 28. Adjuvant nivolumab therapy may be offered to
patients who received neoadjuvant platinum-
27. Clinicians should offer platinum-based adjuvant based chemotherapy (ypT2–T4 or ypN+) or who
chemotherapy to patients with advanced are ineligible for or refuse perioperative cisplatin
pathological stage (pT2–T4 pN0–N3 M0 or pTany (pT3, pT4a, or pN+). (Conditional
N1–3 M0) UTUC after RNU or ureterectomy who Recommendation; Evidence Level: Grade B)
have not received neoadjuvant platinum-based
therapy. (Strong Recommendation; Evidence Two completed RCTs compared adjuvant checkpoint
Level: Grade A) inhibitor therapy versus observation (IMvigor 010) or
placebo (CheckMate 274) following surgery in patients
Adjuvant platinum-based chemotherapy for select with HR non-metastatic urothelial carcinoma (Appendix
patients with UTUC post-RNU is a standard based on V).137, 138 Although the majority of patients in these studies
results from the randomized phase III POUT trial.135 In this underwent radical cystectomy for bladder primaries, 20%
study, 261 chemotherapy-naïve patients were identified of patients in CheckMate 274 and 7% of IMvigor 010
and enrolled post-RNU, with HR patients selected based patients underwent surgery for UTUC, with endpoints
on postoperative stage in non-metastatic patients of pT2– based on the intention to treat population. Inclusion
T4 pN0–N3 M0 or pTany N1–3. In this trial, patients were criteria for both studies were patients with HR urothelial
randomized to platinum chemotherapy day 1 based on cancer defined as pT3, pT4a, or pN+ for patients who had
eligibility (cisplatin, or carboplatin for glomerular filtration not received neoadjuvant cisplatin-based chemotherapy
rate <50 mL/min) with gemcitabine days 1 and 8 for four and ypT2 to ypT4a or ypN+ for patients who had received
planned adjuvant cycles to start within 90 days of RNU. neoadjuvant cisplatin.
The trial was designed to show improved disease-free
survival (DFS) in the chemotherapy versus the In the IMvigor 010 trial, (n=406; 29 with UTUC) planned
observation arm, and after meeting an early efficacy point, one year of adjuvant atezolizumab did not meet the
accrual was halted. At a median follow-up of 30.3 months, primary endpoint of improved DFS compared to
subjects in the adjuvant chemotherapy arm had improved observation (19.4 months versus 16.6 months; HR: 0.89;
DFS (HR: 0.45; 95% CI: 0.30 to 0.68; p=0.0001) 95% CI: 0.74 to 1.08).139 Another study, the phase III
compared with those on observation. Subjects on the randomized adjuvant study of pembrolizumab in muscle
chemotherapy arm had a significantly lower risk of invasive and locally advanced urothelial carcinoma
metastases or death compared to observation (HR: 0.48; including UTUC patients (AMBASSADOR) versus
95% CI: 0.31 to 0.74; log-rank p=0.0007). Side effects of observation trial, has completed accrual and is maturing
platinum chemotherapy were as expected with no grade with data yet to be presented.140
5 events. The completion rate of four adjuvant cisplatin
cycles was low in this dataset at 58%, including 21% of The CheckMate 274 (n=709; 149 with UTUC) study of one
patients who started with cisplatin but switched to year of planned adjuvant nivolumab did meet its co-
carboplatin for post allocation decline in GFR. primary endpoints, with improved DFS (definition per-
protocol included within and outside of the urothelial tract)
29

of 20.8 months (95% CI: 16.5 to 27.6) with nivolumab chemotherapy over adjuvant nivolumab for eligible
versus 10.8 months (95% CI: 8.3 to 13.9) with placebo in patients who did not receive NAC. Scenarios for use of
the intention to treat population.138 The 6-month DFS adjuvant nivolumab include: 1) patients with
benefit of 74.5% with nivolumab and 55.7% with placebo contraindications to platinum-based chemotherapy (e.g.,
(HR: 0.55; 98.72% CI: 0.35 to 0.85; P<0.001) was even poor renal function, performance status, sensorineural
more striking in patients whose tumors expressed PD-L1 hearing loss, neuropathy or congestive heart failure,
(>1%). allergy), 2) patients with HR pathology after NAC, 3)
patients who refuse standard forms of adjuvant
Additionally, non-urothelial tract RFS (77.0% versus chemotherapy after appropriate counseling.
62.7%; HR: 0.72; 95% CI: 0.59 to 0.89), and distant
metastasis free survival (MFS, 82.5% versus 69.8%; HR: 29. In patients with metastatic (M+) UTUC, RNU or
0.75; 95% CI: 0.59 to 0.94) were also improved. In a ureterectomy should not be offered as initial
subgroup analysis of patients with UTUC, there was no therapy. (Expert Opinion)
difference in DFS for renal pelvic cancers (HR: 1.23; 95%
CI: 0.67 to 2.23) or the ureter (HR: 1.56; 95% CI: 0.70 to No clear evidence supports upfront RNU without
3.48) in either arm. The small sample size limits the chemotherapy in the setting of known metastatic (M+)
statistical power to detect a difference, and thus the UTUC. Oncologic outcomes in the metastatic setting are
results from this subgroup analysis in UTUC are strongly determined by response to systemic therapy, and
hypothesis generating only. Based on the strength of the surgical treatment has no demonstrable therapeutic
overall evidence, adjuvant nivolumab was approved for efficacy for cytoreduction or as a single modality in this
UTUC and urothelial carcinoma of the bladder in patients setting. Potential harms such as delay or inability to
with advanced disease identified from post-surgical receive systemic therapy due to consequences of surgery
pathology findings. can significantly and negatively impact oncologic
outcomes and OS in this setting. Therefore, clinicians
With respect to harms, nivolumab was well tolerated and should favor systemic therapy and alternative approaches
similar to placebo with respect to overall AEs (98.9% (i.e., radiotherapy with or without chemotherapy in
versus 95.4%) and grade 3 or higher AEs (42.7% versus selected cases) for inoperable or symptomatic patients
36.8%).107 However, nivolumab was associated with with M+ UTUC.
increased likelihood of treatment-related AEs (77.5%
versus 55.5%) and grade 3 or higher treatment-related Retrospective studies suggesting clinical benefit from
AEs (17.9% versus 7.2%). The most common toxicities in surgery to the primary site in patients with metastatic
the nivolumab group were pruritus (23.1%), fatigue UTUC apply specifically to those who have already
(17.4%), and diarrhea (16.8%); and the most common received first-line chemotherapy or from data sets where
grade 3 or higher AEs were elevations in serum lipase use of peri-operative chemotherapy is poorly
(5.1%) and amylase (3.7%) levels, diarrhea (0.9%), colitis documented, thus limiting interpretation and applicability
(0.9%), and pneumonitis (0.9%). Treatment-related death due to strong selection biases and significant weaknesses
occurred in three patients treated with nivolumab (two due in the data sets.141, 142
to pneumonitis and one due to bowel perforation).
30. Patients with clinical, regional node-positive
Toxicity-related treatment discontinuation was also higher
(cN1-3, M0) UTUC should initially be treated with
from nivolumab compared to placebo (12.8% versus
systemic therapy. Consolidative RNU or
2.0%); most frequently from pneumonitis (1.7%), rash
ureterectomy with lymph-node dissection may be
(1.1%), colitis (0.9%), and increased alanine
performed in those with a partial or complete
aminotransferase level (0.9%). These toxicities are
response. (Expert Opinion)
similar to other checkpoint inhibitor studies with no new
safety signals noted. No adjuvant studies have compared The Panel emphasizes that, in the case of cN1-3 UTUC,
nivolumab to platinum-based chemotherapy regimens. the primary treatment is chemotherapy, and that surgery
with curative intent be considered as a consolidation
Based on the relative strengths of the available data, the
strategy after complete or, in select cases, partial
Panel recommends the use of adjuvant platinum-
response. Supporting data for this statement are derived
30

mainly from studies of platinum-based chemotherapy expectations should be provided and documented.
regimens, and results should be interpreted contextually. Clinical trials, where available, should be discussed with,
sought out, and offered to eligible patients. Multi-modal
Patients with clinically suspicious lymph nodes are approaches include combination of endoscopic
classified as HR unfavorable with likely established locally management to maintain upper and lower tract function
advanced or metastatic disease. These patients with (e.g., stents, nephrostomies, ablation for bleeding and
clinically evident or biopsy proven regional nodal local control) in addition to systemic treatment options if
metastases who demonstrate suitable response to available. Rarely, radiation, angioembolization, or
systemic therapy that converts their disease to a clinical percutaneous ablation for palliation of bleeding can be
state amenable to surgical resection should be offered offered based on anecdotal case report data.144-146
surgical treatment if medically suitable. Pooled data from
comparative outcomes utilizing NAC in patients with SURVEILLANCE AND SURVIVORSHIP
clinically node positive (cN+) disease supports this
approach. Post-Treatment Surveillance
Three reviews included up to six individual studies were
consistent in finding NAC associated with improved
S URVEILLANCE A FTER K IDNEY S PARING
32. Low-risk patients managed with kidney sparing
oncologic outcomes versus NU alone. The largest total
treatment should undergo a follow-up cystoscopy
sample (N=1,252) included a study of patients with cN+
and upper tract endoscopy within one to three
M0 UTUC in the U.S. National Cancer Database
months to confirm successful treatment. Once
(n=720).143 Based on a pooled analysis of adjusted risk
confirmed, these patients should undergo
estimates, NAC was associated with significantly better
continued cystoscopic surveillance of the
OS (5 studies; adjusted HR: 0.53; 95% CI: 0.40 to 0.69)
bladder at least every six to nine months for the
and CSS (2 studies; adjusted HR: 0.39; 95% CI: 0.23 to
first two years and then at least annually
0.67) compared to NU alone. Findings for OS were similar
thereafter. Endoscopy should be repeated at six
in the subgroup of patients with locally advanced tumors
months and one year. Upper tract imaging should
(≥cT3 or cN+; 4 studies; adjusted HR: 0.54; 95% CI: 0.41
be performed at least every six to nine months for
to 0.72; p<0.001). A review including 5 studies common
two years, then annually up to five years.
to all the reviews also found NAC associated with
surveillance after five years in the absence of
improved RFS versus NU (3 studies; HR 0.50; 95% CI:
recurrence should be based on shared decision-
0.37 to 0.66; p<0.0001).
making between the patient and clinician. (Expert
31. Patients with unresectable UTUC (including those Opinion)
who are ineligible or refuse surgery [RNU or
Surveillance regimen should be tailored to disease
ureterectomy]) should be offered a clinical trial or
best supportive care including palliative risk as well as treatment modalities taken.
management (radiation, systemic approach, Patients with LG (LR) UTUC managed with nephron-
endoscopic, or ablative) for refractory symptoms sparing approaches should, at a minimum, undergo
such as hematuria. (Expert Opinion) cystoscopic surveillance three months after endoscopic
treatment, then once again within the first year after
Patients’ localized disease may be deemed unresectable
treatment, then every six to nine months for two years.
or ineligible for extirpative surgical management due to
Upper tract imaging, preferably with CT urogram, should
significant medical comorbidities or other factors including
be done at least every six to nine months for the first
refusal to accept surgical treatment (e.g., solitary kidney).
several years but can then be done annually out to year
Formulating alternative care options should be
five. Follow-up ureteroscopic evaluation should be
approached with multi-disciplinary input with a focus on
performed at a regular interval within the first year but can
realistic goals of care such as providing means of local
then be performed with any symptoms or significant
control for functional preservation (e.g., renal function)
findings on upper tract imaging.
and palliation (e.g., bleeding, infection). Appropriate
patient counseling with an explanation of goals and
31

Risk of recurrence 33. High-risk patients managed with kidney sparing

treatment should undergo a follow-up cystoscopy
Endoscopy and radiographic imaging can be utilized to and upper tract endoscopy with cytology within
evaluate the upper tracts for recurrence within the one to three months. Patients with no evidence of
affected and contralateral system. Although risk of disease should undergo cystoscopic surveillance
recurrence varies on disease characteristics as well as of the bladder and cytology at least every three to
medical therapy (e.g., mitomycin gel), periodic evaluation six months for the first three years and then at
will diagnose disease earlier in the disease progression. least annually thereafter. Endoscopy should be
Of three studies that reported adjusted risk estimates, one repeated at least at six months and one year.
study (n=120) found endoscopic management associated Upper tract imaging should be performed every
with increased risk of any (local, intravesical, or distant) three to six months for three years, then annually
recurrence (adjusted HR: 3.56; 95% CI: 1.73 to 7.35), 84 up to five years. surveillance after five years in the
one study found endoscopic management associated absence of recurrence should be encouraged and
with improved intravesical RFS (adjusted HR: 0.56; 95% based on shared decision-making between the
CI: 0.25 to 1.25),81 and one study found endoscopic patient and clinician. (Expert Opinion)
management associated with increased risk of local
recurrence (adjusted HR: 1.27; p=0.001) but no difference Surveillance regimen should be tailored to disease
in risk of intravesical RFS (adjusted HR: 0.90; p=0.52). 86 risk as well as treatment modalities received.
The follow-up evaluation schedule attempts to balance
the morbidity and cost of follow-up with the risk of disease Some patients with HGT1 or less (HG Ta, T1, or CIS) may
recurrence. Clinicians may elect to increase the intensity be managed with nephron-sparing treatments, such as
of surveillance above the minimum recommendations as endoscopic management, topical therapy, segmental
listed in the guideline according to their assessment of an ureteral resection (including distal ureterectomy) or other
individual patient’s risk and shared decision-making. therapies (e.g., systemic therapy or surveillance).
Patients with HG Ta, T1, or CIS urothelial carcinoma
Risk of metastasis receiving nephron-sparing treatment should undergo
cystoscopic surveillance starting within three months after
Another important reason for disease follow-up is to treatment, continuing every 3-6 months for 3 years, and
evaluate patients for metastatic disease; the likelihood of then every 6-12 months through year 5. Follow-up
which for LG/LR disease is low. Three studies reported ureteroscopy should be performed at least once within
inconsistent results for metastasis: one study82 (n=162) three to six months of endoscopic therapy and
reported higher MFS for patients with LG UTUC who subsequently at the discretion of the clinician.
underwent ureteroscopic management versus patients Ureteroscopy for patients who undergo definitive surgical
with any grade UTUC who underwent NU (5-year MFS management (e.g., SU or distal ureterectomy) should be
84% versus 60%; 10-year MFS 75% versus 54%), one performed at three to six months after resection, and then
study64 (n=453) reported similar 5-year MFS for patients may be performed at the discretion of the clinician, who
with LG UTUC who underwent endoscopic management might prefer cross-sectional excretory imaging in lieu of
versus NU (81% versus 84%, p=0.99), and one study84 ureteroscopy. For patients with HGT1 or less, managed
(n=120) that did not stratify results by UTUC grade by nephron-sparing treatment, upper tract imaging with
reported similar likelihood of distant metastasis for CT urogram and basic metabolic panel (BMP) should be
endoscopic management versus NU (24% versus 27%). performed every 3-6 months for 3 years, then every 6-12
months for 2 years, and annually thereafter. Chest
In an asymptomatic patient with a history of LR UTUC, a
imaging with chest X-ray or CT of the chest is
clinician should perform baseline chest imaging, which
recommended every 6-12 months to evaluate for
can be done by chest X-ray or CT of the chest, but routine
intrathoracic metastasis up to 5 years following last
imaging thereafter is not required.
diagnosis/treatment. As discussed with respect to the
initial characterization of UTUC, MR urography or
retrograde pyelography combined with non-contrast axial
32

imaging may be utilized in patients in whom the treatment compared to those undergoing NU (1.9 years
administration of iodinated contrast is contraindicated. versus 7.8 years; p<0.001 and 73.7% versus 92.4%;
p<0.001; respectively).58 Given the comparatively worse
Risk of recurrence OS, CSS, and MFS rates among patients with HG
disease undergoing nephron-sparing surgery, a risk-
The majority of studies evaluating risk of recurrence with
adapted surveillance scheme should incorporate cross-
nephron-sparing treatment are retrospective
sectional imaging of the abdomen and pelvis as well as
heterogeneous analyses that include both LG and HG
chest imaging to evaluate sites of metastasis.
tumors. A retrospective cohort study of 198 patients with
pTa, pTis, or pT1 disease received either endoscopic 34. Patients who develop urothelial recurrence in the
treatment or RNU, of whom 15% and 25% had HG bladder or urethra or positive cytology following
disease, respectively.42 Mean postoperative creatinine treatment for UTUC should be evaluated for
levels were slightly improved among patients who possible ipsilateral recurrence or development of
received nephron-sparing surgery (1.32 standard new contralateral upper tract disease. (Expert
deviation 0.47] versus 1.64 [SD 0.79; p=0.048]). Among Opinion)
patients receiving endoscopic treatment, recurrence
within the ipsilateral upper urinary tract was higher (25% The development of a recurrence of urothelial carcinoma
versus 1.2%; p<0.001), but recurrence in the bladder was in the lower urinary tract or a positive cytology in the
slightly lower (15% versus 36%; p=0.056). A smaller context of a patient with a history of UTUC should raise
retrospective cohort of 43 patients undergoing either the possibility of recurrent disease in the upper tracts.
endoscopic treatment or RNU, of whom 20% and 91% Thus, patients who develop lower tract recurrence or a
had HG disease, respectively, showed a higher rate of positive cytology without a clear etiology should undergo
bladder recurrence among patients undergoing nephron- an evaluation of the upper tracts. Depending on the
sparing surgery (60% versus 18%; p=0.008).40 Given the clinical scenario this may be via cross-sectional imaging
HR of recurrence in both the upper and lower urinary tract, or retrograde pyelography with or without selective upper
risk-adapted surveillance suggests close monitoring to tract cytology. If these modalities suggest the presence of
reflect a high recurrence risk within this patient population. upper tract involvement, then further evaluation, including
endoscopy, is warranted.
Risk of metastasis
S URVEILLANCE AFTER R ADICAL NU
In studies comparing endoscopic management versus
35. After NU, patients with <pT2 N0/M0 disease
NU, few patients undergoing endoscopic management
should undergo surveillance with cystoscopy and
had HG UTUC, and most patients received nephron-
cytology within three months after surgery, then
sparing treatment did so under palliative or emergent
repeated based on pathologic grade. For LG this
conditions (e.g., bleeding, renal failure).82 In one study,
should repeated at least every six to nine months
ureteroscopic management for HG UTUC in 14 patients
for the first two years and then at least annually
was associated with worse 2-year OS (54% versus 77%),
thereafter. For HG, this should be repeated at
CSS (54% versus 78%), and MFS (34% versus 66%)
least every three to six months for the first three
versus NU in 80 patients (any grade; 71% with HG
years and then at least annually thereafter. Due to
UTUC). At 5 years, survival was 0% in the HG
the metastasis risk and estimated 5% probability
ureteroscopy group, compared with 5-year OS of 58%,
for contralateral disease, cross-sectional imaging
CSS of 64%, and MFS of 60% with surgery. One other
of the abdomen and pelvis should be done within
study found percutaneous endoscopic management
6 months after surgery and then at least annually
associated with worse OS (34.6 months versus 58.0
for a minimum of 5 years. Surveillance after five
months) and CSS (27.8 months versus 56.7 months) in
years in the absence of recurrence should be
the subgroup patients with grade 3 UTUC (n=34).83 In
encouraged and based on shared decision-
another retrospective cohort of 8,304 patients, 633
making between the patient and clinician (See
patients underwent nephron-sparing treatment of whom
Table 6). (Expert Opinion)
39.7% had HG disease. Median OS and 3-year DSS were
worse among those undergoing nephron-sparing
33

Follow up after NU for patients with non-muscle invasive, T2+ MANAGED WITH NU
node-negative UTUC should be largely focused on the 36. For Patients who have undergone NU for >pT2
risk of intravesical recurrence. Two systematic reviews of Nx/0 disease, a clinician should perform
recurrence rates after NU found similar rates of surveillance cystoscopy with cytology at three
intravesical recurrence after NU to be approximately 29% months after surgery, then every three to six
with a median time to recurrence of 6-12 months147 or 22 months for 3 years, and then annually thereafter.
months.148 The study by Kapoor et al. also summarized Cross-sectional imaging of the abdomen and
the overall risk of recurrence to the contralateral upper pelvis with multiphasic contrast-enhanced CT
tract at 2.2% (range 0% to 4.6%; mean follow-up 46.7 urography should be performed every three to six
months).147 Locke et al. led a large Canadian study of over months for years one and two, every six months
a 1,000 patients that found similar results with a local at year three, and annually thereafter to year five.
recurrence rate (both bladder and upper tract) of 24% with A clinician should perform chest imaging,
a median time to recurrence of 7 months.149 That study preferably with chest CT, every 6-12 months for
also noted that 91% of the local recurrences were the first 5 years. Beyond five years after surgery
identified within the first 2 years, while late recurrences in patients without recurrence, ongoing
did occur as late as 150 months after surgery. Therefore, surveillance with cystoscopy and upper tract
in the first two years after NU, there should be regular imaging may be continued on an annual basis
attention paid to monitoring for intravesical recurrence according to principles of shared/informed
through regular cystoscopic surveillance. After two years, decision-making. (Expert Opinion)
the frequency can be significantly reduced though, as with
non-muscle invasive bladder cancer, how long Regional Recurrences (Bladder) following NU
surveillance should be continued is not clear.150 Periodic
Follow-up after NU for non-metastatic node-negative pT2
imaging of the upper tracts should be undertaken given
and higher disease requires surveillance for local and
the risk of recurrence to the contralateral upper tract,
regional recurrence, intravesical recurrences, and distant
preferably with cross-sectional imaging such as CT
metastases. A meta-analysis of 59 studies147 evaluating
urogram, though the rate is low enough that this can be
recurrences following NU reported a 29% risk of
done annually after NU.
intravesical recurrence within a median 6-12 months after
The Locke et al. study broke down the risk of regional or RNU. A 2016 systematic review of 18 studies enumerated
distant recurrence by grade and stage when examining key risk factors for intravesical recurrence including male
the risk of locoregional or distant metastases.149 Patients sex (HR: 1.37; p<0.001), previous bladder cancer (HR:
with less than pT2 or pN+ disease were considered either 1.96; p<0.001), preoperative CKD (HR: 1.87; p=0.002),
LR (pTa-T1, pN0, LG, no LVI, and not multifocal) or positive preoperative urinary cytology (HR: 1.56;
intermediate (pTa-T1, pN0 and HG, LVI present, or p<0.001), ureteral tumor site (HR: 1.27, p<0.001),
multifocal). The 3-year estimated freedom from regional multifocality (HR: 1.61; p=0.002), invasive pathologic T-
or distant metastases were 93% and 87% for these low- stage (HR: 1.38; p<0.001), presence of necrosis (HR:
and intermediate-risk groups, respectively. The rate of 2.17; p=0.02), laparoscopic approach (HR: 1.62;
intrabdominal recurrences in LR patients from this study p=0.003), extravesical bladder cuff removal (HR: 1.22;
was very low while in intermediate-risk patients it was p=0.02), and positive surgical margins (HR 1.90;
17%, with most occurring within the first 2 years. Thus, p=0.004).148 Additional independent risk factors for
periodic imaging of the abdomen and pelvis is warranted, intravesical recurrence included having positive surgical
especially for those HG disease, LVI or tumor margins (HR: 3.36; 95% CI: 1.36 to 8.33) and prior
multifocality, particularly for the first two years. The risk of ureteroscopic biopsy (HR: 1.39; 95% CI: 0.88 to 2.19). 151
lung metastases for patients with less than pT2 or pN+
disease is overall low but can occur in those with HG
disease so periodic chest imaging (Table 6) should be
undertaken and can be done via chest x-ray or CT of the
chest, though the former is likely sufficient, less costly,
and associated with less radiation exposure.
34

T ABLE 6: S URVEILLANCE A FTER C OMPLETE T REATMENT

The following surveillance schedules are recommended in the setting of complete treatment where no residual or recurrent tumor is identified or clinically
suspected. Earlier intervals of follow-up endoscopy may be used in cases of concern for incomplete treatment (e.g., larger tumors, more difficult access,
poor visibility, disease biology). The Panel recognizes the limitations of the data on tumor recurrence and optimal intervals of follow-up which require
further study. Any clinical findings of new or worsening disease should prompt re-evaluation.
Year 1 2 3 4 5
Month 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 >60 months
Kidney-Sparing, Low-Risk
Cystoscopy, Cytology - X X - X - X - X - - - X - - - X - - - X -
Upper Tract Endoscopy - X X - X - - - - - - - - - - - - - - - - -
Cross-Sectional Imaging* - X - - X - X - X - - - X - - - X - - - X -
Chest Imaging - - - - X - - - - - - - - - - - - - - - - -
BMP - - - - X - - - X - - - X - - - X - - - X -
Kidney-Sparing, High-Risk
Cystoscopy, Cytology - X X - X - X - X - X - X - - - X - - - X O
Upper Tract Endoscopy - X X - X - - - - - - - - - - - - - - - - -
Cross-Sectional Imaging* - X X - X - X - X - X - X - - - X - - - X O
Chest Imaging - - X - X - X - X - - - X - - - - - - - - -
BMP - - - - X - - - X - - - X - - - X - - - X -
Post Nephroureterectomy, <pT2, N0/NX
Cystoscopy, Cytology - X X O X - X - X - - - X - - - X - - - X -
Cross-Sectional Imaging* - - X - X - - - X - - - X - - - O - - - O -
Chest Imaging - - - - X - - - - - - - - - - - - - - -
BMP - X - - X - - - X - - - X - - - X - - - X -
Post Nephroureterectomy, ≥pT2
Cystoscopy, Cytology - X X - X - X - X - X - X - - - X - - - X O
Cross-Sectional Imaging* - X X - X - X - X - - - X - - - X - - - X O
Chest Imaging - X X - X - X - X - - - X - - - X - - - X -
BMP - X - - X - - - X - - - X - - - X - - - X -
* Cross-sectional imaging of the abdomen and pelvis with CT or MRI should be performed with contrast when possible
X Recommended (Should be performed in the associated time interval)

O Optional (May be performed in the associated time interval)
- As indicated (Performed in the associated time interval for clinical indications)
A large Canadian study (n=1,029) similarly identified a regarding the risk of bladder recurrence according to the
26% risk of urothelial (bladder or contralateral upper tract) location of the primary tumor. Given the substantial risk of
recurrence with a mean time to recurrence of 7 months.149 local (bladder) recurrences within the first years following
Post-NU bladder recurrences were observed in 21%, NU, risk adapted surveillance with cystoscopy and urine
26%, and 36% of patients with UTUC of the renal pelvis, cytology at routine intervals is indicated to facilitate
ureter, or both, respectively. In patients with HR disease, prompt detection of bladder recurrences.
defined as ≥pT2 or pN+ and any grade, with or without
LVI or multifocality, bladder recurrences were observed in Locoregional recurrence, retroperitoneal nodal and
53% of patients compared to 14% and 33% for low- and distant metastases following NU
intermediate-risk disease; with 52% of recurrences in the
In the previously mentioned meta-analysis of 59
bladder in the intermediate-risk categories occurring in
studies147 evaluating recurrences following NU, in
the first year following NU. There are conflicting data
addition to the risk of intravesical recurrence, they
36

reported recurrences of the retroperitoneum or pelvis not be obtained routinely but may be selectively
occurred in 4.6% of patients within an average 32.7 considered for patients who are at risk for metastatic
months, and distant metastases occurred in 16.4% within recurrence and are not able to have contrast enhanced
an average of 46.8 months. Retroperitoneal lymph node CT and MRI. Finally, patients with findings suggestive of
metastasis occurred in 5.2% of patients within a mean of metastatic UTUC should be evaluated to define the extent
46.8 months), while lung, liver, and bone metastases of disease and referred to medical oncology for further
were observed in 4.8%, 4.1%, and 3.7% of patients, management.
respectively. The median time to metastases was
13months to 16 months (range 1 month to 50 months In addition to following patients for cancer recurrence or
postoperatively). The large Canadian study (n=1,029) metastasis, clinicians should monitor patients for the
mentioned previously found 24% of patients experience sequelae of NU. Following NU for HR UTUC, the Panel
locoregional (in the nephrectomy bed or retroperitoneal recommends that patients should undergo periodic
lymph nodes) or distant (lung, bone, liver, brain, or other) laboratory assessment including serum creatinine level,
recurrence with a mean time to recurrence of 8 months.149 eGFR, and urinalysis. Other laboratory evaluations (e.g.,
In this analysis, 91% of local recurrences were diagnosed CBC, LDH, liver function tests, and alkaline phosphatase)
in the first 2 years, though late local recurrences (up to may be obtained at the discretion of the clinician or if
150 months) were observed. Post-NU locoregional and advanced disease is suspected. In patients who develop
distant recurrences were observed in 21%, 24%, and progressive renal insufficiency or proteinuria should be
31%, respectively. In patients with intermediate- and HR referred to nephrology.
UTUC, while rare, the vast majority of recurrences to the
nephrectomy bed, liver, and distant metastases to the Survivorship
lungs and bones were observed in patients with
37. For patients with reduced or deteriorating renal
intermediate- and HR disease within 18-24 months
function following NU or other intervention,
following NU. Risk factors for recurrence following NU
clinicians should consider referral to nephrology.
include risk factors associated with increased risk of
(Expert Opinion)
recurrence were multifocality, stage T3-4, grade G3, and
presence of lymph node metastasis; UTUC site in ureter Referral to nephrology should be considered for patients
versus renal pelvis was not an independent predictor. 152 with eGFR less than 45 mL/min/1.73m 2, confirmed
Given this risk of locoregional recurrence and metastasis proteinuria, diabetics with preexisting CKD, or whenever
in patients with > pT2 UTUC following NU, risk-adapted eGFR is expected to be less than 30 mL/min/1.73m 2 after
routine surveillance with contrast-enhanced cross- intervention.
sectional imaging and urography is recommended, with
decreasing intensity in years three to five, and The long-term impact of renal dysfunction increases risks
subsequent follow-up surveillance recommended of osteoporosis, anemia, metabolic and cardiovascular
according to principles of informed/shared decision- disease, hospitalization and death. Effective treatment
making. strategies are available to slow the progression of CKD
and reduce cardiovascular risks, and therefore timely
Of note, brain metastases are rare following NU, but have identification of progressive renal dysfunction and/or
been observed only in patients with a prior history of HR proteinuria can provide opportunity for medical
UTUC, within an average of 18 months of NU.147 Patients intervention when indicated. The two formulas for
undergoing follow-up for HR UTUC following NU with monitoring eGFR commonly reported in the contemporary
acute neurological signs or symptoms should undergo literature at this time are the Modification of Diet in Renal
prompt neurologic evaluation with cross-sectional Disease and CKD – Epidemiology Collaboration (CKD-
imaging of the brain and/or spine by CT or MRI. EPI) equations.
For patients undergoing follow-up for treated UTUC, 38. Clinicians should discuss disease-related
additional site-specific imaging can be ordered as stresses and risk factors and encourage patients
warranted according to clinical symptoms suggestive of with urothelial cancer to adopt healthy lifestyle
local recurrence or metastatic spread. PET scans should habits, including smoking cessation, exercise,
37

and a healthy diet, to promote long-term health There is no one-size-fits-all approach to treating UTUC,
benefits and quality of life. (Expert Opinion) and further refinements are needed for characterizing
aspects of disease risk and biology to help direct care.
Risk factors such as smoking are associated with Recent studies have identified significant genomic
advanced disease stage, recurrence and worse CSM distinctions between primary UTUC and primary bladder
among patients with UTUC, with the highest risk among cancers, namely a higher prevalence of activating FGFR3
current smokers.153 Therefore, clinicians should discuss mutations (fibroblast growth factor receptor 3) in UTUC as
and facilitate smoking cessation with patients at the time a key driver for tumorigenesis. Investigating the key
of diagnosis and treatment. UTUC is also associated with question as to why this occurs more in upper tract tumors
metabolic syndrome and obesity, with obesity adversely may help lead toward identifying causative factors and the
impacting disease-specific outcomes among patients development of preventative strategies, particularly in HR
undergoing RNU.154, 155 Clinicians should, therefore, populations such as LS. Genomic markers may also
encourage patients to adopt healthy lifestyle habits prove useful as less non-invasive biomarkers of tumor
regarding exercise and a healthy diet to promote long- grade and stage and for identifying potential pathways for
term health benefits and quality of life. Finally, clinicians directed treatment, such as FGFR3 inhibition. Other
should work with patients and their primary care providers urinary biomarkers investigated to identify UTUC have
to ensure that comorbidities are optimally managed suggested improved accuracy over urinary cytology, such
throughout the course of care for UTUC and during as DNA methylation assays, RNA panels and cell-free
surveillance to maximize quality of life during survivorship. DNA.156-160 Further evaluation of these panels in the
clinically relevant setting of screening, evaluation and
Future Directions surveillance seem warranted. Enhancing diagnostic
capabilities utilizing the limited tissue samples yielded in
Urothelial cancers can arise anywhere in the urinary tract UTUC would improve risk stratification and refine
and anatomical features can affect management. treatment planning while facilitating less invasive follow-
Techniques and approaches for addressing tumors in the up approaches to monitor for recurrence or response to
lower urinary tract (bladder and urethra) have several treatment. Like surveillance for lower tract disease,
advantages for standardizing management strategies urinary biomarkers may provide a less invasive and easily
since they are more easily accessed, clinically staged, accessible means to refine post-treatment follow-up for
locally treated, and readily followed than tumors arising in urothelial recurrence with better-informed indications and
the upper tract. The large variety of clinical scenarios timing for endoscopic surveillance procedures.
encountered in upper tract disease coupled with limited
Instrumentation and Ablative Treatments
access and instrumentation as well as risks of significant
comorbidities and organ dysfunction present major Improvements in flexible digital endoscopes have greatly
challenges and barriers to management that are only improved visualization and access to the upper urinary
recently being recognized and confronted through tract to reach and identify tumors. Instrumentation to allow
concerted collaborative efforts required in this rare for effective and safe tissue sampling has been much
disease. This last feature also underscores the most slower to develop – leaving clinicians to struggle using
serious unmet need that this guideline seeks to address, techniques that are highly skill-dependent and inefficient.
which are the large education gaps and variation in Newer devices are in development that may leverage the
clinical care surrounding a highly lethal malignancy, rarer ability of robotic endoscopy with snake-like instruments to
than testis cancer, with concentrated expertise in few offer better and more precise endoscopic surgical
dedicated centers. Educating clinicians about the current capabilities. The advent of new therapies such as reverse
state of medical knowledge, highlighting important thermo-hydrogel preparation of mitomycin have provided
nuances of management, and teaching specialized an important new means of treating low-risk tumors.
techniques necessary for safe and successful treatment Additional treatments to support kidney sparing
is a pressing priority. approaches are yet needed, especially for small volume
Biology and Biomarkers HG cancers. Energy devices such as the thulium:YAG
laser have recently been approved and added to thermal
38

ablative capabilities. New photodynamic treatments are

also now in Phase III clinical trials to offer additional
options for treatment. While these primary treatment
options have great therapeutic potential, urothelial
recurrences are a subsequent issue in follow-up which
other groups are also addressing through clinical trials
using approaches such as instilled topical
chemotherapeutics.
Multi-Disciplinary Care
Managing patients with UTUC requires a multi-
disciplinary team approach to optimize overall care.
Access to medical genetics specialists is important for
screening and counseling patients with LS – a population
just beginning to be recognized and gain appropriate
attention for the challenges in care. Improvements in
surgical management have limits when disease biology
exceeds localized treatment requiring systemic therapies.
The integration of medical oncology expertise is therefore
critical to provide risk-appropriate adjunctive care to
improve cancer specific outcomes and quality of life.
Clinical trials with close collaboration between medical
oncologist and urologist are addressing some of the key
issues of multi-disciplinary care and listed below. The
developing field of nephro-oncology also plays a
significant role in treatment planning for these vulnerable
patient populations who face the prospect of severe renal
functional decline and require special attention.
Partnerships among these specialties are developing in
centers with dedicated UTUC programs to centralize and
standardize care – a strategy that has proven effective in
optimizing outcomes for other rare cancers that are prone
to mismanagement.
39

NU Nephroureterectomy
Abbreviations OHSU Oregon Health & Science University
OS Overall Survival
AE Adverse Event
PPV Positive Predictive Value
ASCO American Society of Clinical Oncology
PGC Practice Guidelines Committee
AUA American Urological Association
PFS Progression-Free Survival
AUAER American Urological Association
RNU Radical Nephroureterectomy
Education and Research
RCT Randomized Control Trial
BCG Bacillus Calmette–Guérin
RFS Recurrence-Free Survival
BMP Basic Metabolic Panel
ROB Risk of Bias
BCE Bladder Cuff Excision
SQC Science and Quality Council
BOD Board of Directors
SU Segmental Ureterectomy
CSS Cancer-Specific Survival
SEER Surveillance, Epidemiology, and End
CSM Cancer-Specific Mortality
Results
CIS Carcinoma in Situ
TURBT Trans Urethral Resection of Bladder
CDC Centers for Disease Control and
Tumor
Prevention
US Ultrasound
CKD Chronic Kidney Disease
UTUC Upper Tract Urothelial Cancer
CRC Colorectal Cancers
CT Computerized Tomography
CI Confidence Interval
DM Diabetes Mellitus
DFS Disease-Free Survival
ESRD End-Stage Renal Disease
eGFR Estimated Glomerular Filtration Rate
FNA Fine-Needle Aspiration
FISH Fluorescence In Situ Hybridization
HNPCC Hereditary Nonpolyposis Colorectal
Cancer
HG High-Grade
HR High-Risk
HS High-Stage
HTN Hypertension
IHC Immunohistochemical
LG Low-Grade
LR Low-Risk
LND Lymph Node Dissection
LVI Lymphovascular Invasion
LS Lynch Syndrome
MR Magnetic resonance
MMR Mechanisms of Mismatch Repair
MSI Microsatellite Instability
MMC Mitomycin-C
MDCTU Multidetector Computed Tomography
Urography
NCCN National Comprehensive Cancer
Network
NPV Negative Predictive Value
NAC Neoadjuvant Chemotherapy
40

UPPER TRACT UROTHELIAL CARCINOMA (UTUC) PANEL,

CONSULTANTS, AND STAFF
Panel CONFLICT OF INTEREST DISCLOSURES
Jonathan A. Coleman, MD (Chair) All panel members completed COI disclosures.
Memorial Sloan Kettering Disclosures listed include both topic– and non -topic-
related relationships. Panel members not listed below
Peter E. Clark, MD (Vice- Chair) have nothing to disclose.
Atrium Health
Consultant/Advisor: Sam S. Chang: GLG, Janssen,
Sam S. Chang, MD, MBA (PGC Representative) Pfizer, Urogen, Virtuoso Surgical, mIR, Prokarium, KDx
Vanderbilt Health Diagnostics, Tu Therapeutics, Lantheus, Merck, Pacific
Edge, Nonagen, Astra-Zeneca; Jean H. Hoffman-
Jean Hoffman-Censits, MD Centsis: Seattle Genetics, Foundation Medicine, Astra-
Johns Hopkins Medicine Zeneca; Girish S. Kulkarni: Janssen, Merck, Ferring,
Theralase, Abbvie, Roche, TerSera, EMD Serano;
Girish S. Kulkarni, MD, PhD Surena F. Matin: Johnson & Johnson, Merck, Fujifilm;
University of Toronto Phillip M. Pierorazio: Ethicon (J&J); Angela M. Smith:
Merck, Urogen
Surena F. Matin, MD
MD Anderson Cancer Center Scientific Study or Trial: Sam S. Chang: NIH, NantBio;
Jonathan A. Coleman: Angiodynamics, Metabolon;
Phillip M. Pierorazio, MD Jean H. Hoffman-Centsis: Genentech; Girish S.
Penn Medicine Kulkarni: Astra- Zeneca, Bristol Myers Squibb, Merck,
Theralase, Verity Pharmaceuticals; Sarah P. Psutka:
Aaron M. Potretzke, MD Janssen; Jay D. Raman: Urogen Pharma, Pacific Edge
Mayo Clinic Biotechnologies, Steba Biotech; Angela M. Smith:
PCORI, BCAN
Sarah P. Psutka, MD
UW Medicine Health Publishing: Sam S. Chang: Uro Today; Phillip
M. Pierorazio: Wolters Kluwer; Sarah P. Psutka: Bladder
Jay D. Raman, MD Cancer
Penn State Health
Leadership Position: Girish S. Kulkarni: Bladder
Angela B. Smith, MD Cancer Canada; Phillip M. Pierorazio: Testicular Cancer
UNC School of Medicine Awareness Foundation; Sarah P. Psutka: European
Urology
Laura Smith (Patient Advocate)
Stock Option: Jay D. Raman: American Kidney Stone
Consultants Management, United Medical Systems, Inc.
Roger Chou, MD
David Buckley, MD PEER REVIEWERS
Staff We are grateful to the persons listed below who

Erin Kirkby, MS contributed to the Guideline by providing comments
Leila Rahimi, MPH during the peer review process. Their reviews do not
Brooke Bixler, MPH necessarily imply endorsement of the Guideline.
Sennett K. Kim
Chelsi Matthews AUA (Board of Directors, Science and Quality
Council, Practice Guidelines Committee, Journal of
Urology)
Erin Bird, MD
41

Stephen Boorjian, MD DISCLAIMER

Benjamin Breyer, MD
John D. Denstedt, MD This document was written by the Early Detection of
David Ginsberg, MD Prostate Cancer Panel of the American Urological
Suzanne Merrill, MD
Association Education and Research, Inc., which was
Edward Messing, MD
Vernon Pais, MD created in 2021. The Practice Guidelines Committee
Charles R. Powell II, MD (PGC) of the AUA selected the Panel Chair. Panel
Hassan Razvi, MD members were selected by the Panel and PGC Chair.
Jaspreet Sandhu, MD
Nirmish Singla, MD Membership of the panel included specialists with specific
Thomas F. Stringer, MD expertise on this disorder. The mission of the panel was
to develop recommendations that are analysis-based or
External Reviewers (Non-AUA Affiliates)
consensus-based, depending on panel processes and
Adam Calaway, MD available data, for optimal clinical practices in the early
Piyush Agarwal, MD detection of prostate cancer setting.
Riccardo Autorino, MD
Mark Bandyk, MD Funding of the panel was provided by the AUA. Panel
David Chen, MD members received no remuneration for their work. Each
Paul Crispen, MD member of the panel provides an ongoing conflict of
Rian Dickstein, MD interest disclosure to the AUA.
Hooman Djaladat, MD
Saum Ghodoussipour, MD While these guidelines do not necessarily establish the
Brian Hu, MD standard of care, AUA seeks to recommend and to
Scott Hubosky, MD
encourage compliance by practitioners with current best
Janet Kukreja, MD
Costasw Lallas, MD practices related to the condition being treated. As
Aaron A. Laviana, MD medical knowledge expands and technology advances,
Jennifer Anne Linehan, MD the guidelines will change. Today these evidence-based
Amy Luckenbaugh, MD guidelines statements represent not absolute mandates
Timothy D. Lyon, MD but provisional proposals for treatment under the specific
Reza Mehrazin, MD
conditions described in each document. For all these
Raymond Pak, MD
Firas Petros, MD reasons, the guidelines do not pre-empt physician
Sima Porten, MD judgment in individual cases.
Michael Seiba, MD
Ahmad Shabsigh, MD Treating physicians must take into account variations in
Dinesh Singh, MD resources, and patient tolerances, needs, and
Woodson W. Smelser, MD preferences. Conformance with any clinical guideline
Massimiliano Spaliviero, MD does not guarantee a successful outcome. The guideline
William Tabayoyong, MD text may include information or recommendations about
Mark D. Tyson, MD
certain drug uses (“off label”) that are not approved by the
Christopher Wallis, MD
Heinric Williams, MD Food and Drug Administration (FDA), or about
Joseph Zabell, MD medications or substances not subject to the FDA
Harras B. Zaid, MD approval process. AUA urges strict compliance with all
government regulations and protocols for prescription and
Public Commenters (Via public notice on AUA use of these substances. The physician is encouraged to
website)
carefully follow all available prescribing information about
Kirll Shiranov, MD
indications, contraindications, precautions and warnings.
These guidelines and best practice statements are not in-
tended to provide legal advice about use and misuse of
these substances.
42

Although guidelines are intended to encourage best

practices and potentially encompass available
technologies with sufficient data as of close of the
literature review, they are necessarily time-limited.
Guidelines cannot include evaluation of all data on
emerging technologies or management, including those
that are FDA-approved, which may immediately come to
represent accepted clinical practices.
For this reason, the AUA does not regard technologies or

management that are too new to be addressed by this
guideline as necessarily experimental or investigational.
43

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UTUC Unabridged FINAL 060923

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American Urological Association (AUA)/

A PPROVED BY THE AUA DIAGNOSIS AND MANAGEMENT OF NON-METASTATIC

Copyright © 2023 American Urological Association Education and Research, Inc. ®

Upper Tract Urothelial Carcinoma (UTUC)

Kidney Sparing Management

Copyright © 2023 American Urological Association Education and Research, Inc. ®

Upper Tract Urothelial Carcinoma (UTUC)

Lymph Node Dissection (LND)

Neoadjuvant/Adjuvant Chemotherapy and Immunotherapy

Copyright © 2023 American Urological Association Education and Research, Inc. ®

Upper Tract Urothelial Carcinoma (UTUC)

SURVEILLANCE AND SURVIVORSHIP

S URVEILLANCE A FTER K IDNEY S PARING

S URVEILLANCE AFTER R ADICAL NU

Copyright © 2023 American Urological Association Education and Research, Inc. ®

Upper Tract Urothelial Carcinoma (UTUC)

T2+ MANAGED WITH NU

Copyright © 2023 American Urological Association Education and Research, Inc. ®

Upper Tract Urothelial Carcinoma (UTUC)

Copyright © 2023 American Urological Association Education and Research, Inc. ®

Upper Tract Urothelial Carcinoma (UTUC)

Table 1: Strength of Evidence Definitions

B Moderate  Moderately confident in the effect estimate

C Low  Confidence in the effect estimate is limited

Very Low  Very little confidence in the effect estimate

Copyright © 2023 American Urological Association Education and Research, Inc. ®

Upper Tract Urothelial Carcinoma (UTUC)

Copyright © 2023 American Urological Association Education and Research, Inc. ®

Upper Tract Urothelial Carcinoma (UTUC)

Conditional -Benefits = Risks/Burdens -Benefits = Risks/Burdens -Balance between Benefits &

Copyright © 2023 American Urological Association Education and Research, Inc. ®

Upper Tract Urothelial Carcinoma (UTUC)

diagnostic accuracy of US for UTUC alone, one study of

Copyright © 2023 American Urological Association Education and Research, Inc. ®

Upper Tract Urothelial Carcinoma (UTUC)

Copyright © 2023 American Urological Association Education and Research, Inc. ®

Upper Tract Urothelial Carcinoma (UTUC)

Table 3: Standardized Upper Tract Endoscopy Suggested Reporting Elements

Copyright © 2023 American Urological Association Education and Research, Inc. ®

Upper Tract Urothelial Carcinoma (UTUC)

Copyright © 2023 American Urological Association Education and Research, Inc. ®

Upper Tract Urothelial Carcinoma (UTUC)

Copyright © 2023 American Urological Association Education and Research, Inc. ®

Upper Tract Urothelial Carcinoma (UTUC)

Two successive generations should be affected

One should be a first-degree relative of the other two

One should be diagnosed before age 50

Revised Bethesda Tumors in families that meet Amsterdam II criteria

Presence of synchronous, metachronous colorectal, or other LS-associated tumors, regardless of age

Copyright © 2023 American Urological Association Education and Research, Inc. ®

Upper Tract Urothelial Carcinoma (UTUC)

10. Following standardized assessment,

Copyright © 2023 American Urological Association Education and Research, Inc. ®

Upper Tract Urothelial Carcinoma (UTUC)

Copyright © 2023 American Urological Association Education and Research, Inc. ®

Upper Tract Urothelial Carcinoma (UTUC)

Table 5: Presurgical Clinical Risk Categories

** Concomitant or prior history of lower tract involvement.