This document was created in January 2024 for original publication into the AUA Medical Student Curriculum. This document will continue to be periodically updated to reflect the growing body of literature related to this topic.

Objectives

This section of the AUA Medical Student Education Section reviews upper tract urothelial cancer (UTUC), while also providing information on relevant physiological processes of the upper urinary tract. We also aim to share current supporting evidence for disease management and detection as well as future directions of UTUC.

1. Explore UTUC characteristics epidemiology and risk factors
2. Explain upper urinary tract anatomy and physiology
3. Present a general guideline for UTUC detection and risk stratification
4. Highlight future directions in UTUC research and care

Introduction

Upper Tract Urothelial Carcinoma (UTUC) is a relatively uncommon subtype of urothelial cancer defined by its involvement of the renal pyelocaliceal cavities and ureter. It contributes to only 5–10% cases of diagnosed urothelial cancer.¹ In the United States, the incidence of cancers involving the upper tract as a gross aggregate of ureteral and renal pelvic tumors is about 7,000 cases a year, and continues to rise with improved detection.^2,3 It is important to differentiate from renal cell cancer, which is a completely different subtype of “kidney cancer” but can be confusing to patients.

Most patients who present with UTUCs have invasive disease at initial diagnosis.⁴ Approximately 9% of patients with UTUC present with metastasis, which stands in contrast to urothelial cancer of the bladder^4,5 Therefore, though there are shared characteristics with urothelial bladder cancer that we will discuss, we also hope to shed light on the distinct prognostic, therapeutic, and diagnostic considerations for urothelial cancer involving the upper tract.

Several leading organizations including the American Urologic Association (AUA), National Comprehensive Cancer Network (NCCN), and European Association of Urology (EAU), have developed guidelines specifically tailored to the unique nature of UTUC. These guidelines provide current evidence-based recommendations for diagnosing, stratifying risk, and conducting surveillance, all aimed at improving outcomes for non-metastatic UTUC patients. For the most recent guidelines, please visit the respective institutional websites.

Upper Tract Anatomy

The upper tract comprises the renal pelvis, renal calyces, and the ureters, all situated orthotopically within the retroperitoneum (Figure 1). The upper urinary tract structures have their origins in the mesoderm and are associated with the development of the ureteric bud from the wolffian duct. Conversely, the lower urinary tract derives from the endoderm. So, while the upper urinary tract is anatomically continuous and contains the same urothelial cell lining as the lower urinary tract bladder, they possess embryologically distinct origins.

The upper urinary tract also has a more varied blood supply and lymph node drainage. The upper third of the ureter, along with the renal calyx and pelvis, gets its blood supply from the renal arteries (as shown in Figure 1). The middle third gets vascular supply by tributaries of the common iliac arteries and the gonadal arteries, which branch from the abdominal aorta. As for the distal third of the ureter, it receives blood from branches of the internal iliac artery.

In terms of lymph nodes that correspond to UTUC, the perihilar and retroperitoneal nodes are involved with the first third of the ureter, while the pelvic nodes drain the mid- and distal ureter. It's important to note that the tumor laterality does not impact nodal (N) classification. Unlike some other malignancies, the lymphatic drainage is often not predictable and can skip nodal groups.

Given the location of UTUC and the anatomic length that traverses, it can metastasize various locations including lung, bone, spinal cord, liver, and less commonly, the brain.⁶ 

Figure 1: The top left image illustrates the typical arrangement of pelvicalyceal anatomy, where 9-12 minor calyces converge into 3-4 major calyces. In the top right image, some aspects of ureteral basic blood supply and the course of the ureters in the retroperitoneum are depicted. Finally, the bottom panel provides key histological information, showing that the bladder has a relatively thick and woven detrusor muscle layer, while the muscular layer in the upper urinary tract is comparatively thinner. Source: Teach me Anatomy LLC, and https://www.mccc.edu/~falkowl/documents/UrinarySystem.pdf

Urothelial Cell Function and Implications for UTUC

Unlike lower urinary tract cancers, 90% of upper tract malignancies are urothelial cell by histology. They are less likely to be associated with squamous cell carcinoma, adenocarcinoma, or small cell cancer histology compared to bladder cancer, though they have been described in rare occurrences.⁷

Urothelium is a distinctive type of epithelial cell that forms the lining of the entire luminal urinary tract, including the renal calyces, ureters, bladder, and urethra. In the upper urinary tract, the urothelium plays a crucial role as a watertight barrier, facilitating the safe and antegrade flow of urine into the bladder (Figure 1).⁸ In contrast to epithelial cells found in the skin or gastrointestinal tract, most urothelial cells are in a 'quiescent' state of the G0 phase of mitosis. However, unlike terminal G0 cells such as neurons, these urothelial cells still possess the ability to leave G0, divide, and repair damaged DNA when faced with mechanical trauma, hypoxia, thermal and chemical exposures.⁹ 

Urothelium can be examined histologically as multilayer epithelial cell structure with no intervening blood vessels or nerve endings containing an apical, intermediate, and basal layer (Figure 2). The apical layer, in direct contact with urine, comprises modified, larger dome-shaped cells referred to as 'umbrella cells,' named for their tight junctions that create a waterproof barrier (Figure 2).¹⁰ Under the urothelium is the basement membrane acts as both a physical barrier to the underlying lamina propria. This lamina propria is crucial for upper tract function due to its blood vessels and nerves (Figure 1).

When tumors penetrate the basement membrane and enter the lamina propria, they gain access to lymphatics and blood vessels, which vary based on the anatomic level that the initial tumor develops (Figure 2). Beneath the lamina propria, a thin layer of smooth muscle, known as the 'muscularis propria,' spans the entire upper urinary tract, facilitating the propulsion of urine into the bladder in response to pressure (Figure 1). The placement of a double J stent in the ureter serves various purposes for urologists, including the treatment or pre-treatment of ureteral obstruction. While this improves net antegrade urine flow, it can potentially lead to ureteral reflux during bladder contractions by overriding this natural peristaltic anti-reflux mechanism of the ureter and by maintaining the patency of the ureterovesical junction (UVJ).¹¹

Unlike the bladder, the ureter and renal pelvis do not have an outer serosa layer because they are entirely retroperitoneal structures. Additionally, the smooth muscle layer in the upper urinary tract is thinner compared to the detrusor muscle in the bladder. (Figure 1).

Figure 2: Top panel: A revisualization of the layers in the upper urinary tract concerning tumor invasion. Source:  https://www.mdpi.com/2075-4418/13/5/1004 Bottom right and left panels: Urothelium magnified at 40x with depiction of urothelial layers and apical 'umbrella cells' (green arrows) as well as basal urothelium overlying the lamina propria in a mouse bladder. Here, oncogene CDKN2a RNA expression is also depicted in red punctae - RNA scope. Source: Antony, 2023, figures reproduced with permission from Al Nagar, Iman

Theories of UTUC pathophysiology

Identifying distinct mechanisms for bladder and upper tract urothelial cancer is challenging owing to its the tendency to develop multiple discontinuous foci along the urinary tract (Figure 3). The 'field effect' theory suggests that urothelial cancer may be present but grossly undetectable throughout urinary tract tissue. Clonal accumulation of mutations occurs before the patient experiences symptoms or observable disease.¹² This is supported by evidence showing that primary tumors in bladder cancer share similar pathological, histological, and genetic features with cases where UTUC develops following an initial diagnosis of bladder cancer or carcinoma in situ (CIS).^4,12–16

Low-grade primary UTUC also share similar genetic mutations with urothelial bladder cancer.¹⁷ Genes involved in UTUC include CDKN2a, which promotes cell proliferation (Figure 2), and FGFR3 overexpression, a modulator of cell proliferation and growth.^18,19 However, high-grade UTUC frequently presents p53 mutations, a tumor suppressor gene and major regulator of the cell cycle, found in more aggressive UTUC.²⁰ This gene has also been implicated in some environmental exposures, namely aristolochic acid induced nephropathy in rural areas of the Balkan sea and Asia.²¹  Two gene polymorphisms have also since been identified as distinct and specific to UTUC independent of age, gender, smoking habit and ethnicity.²²

Mutations in mismatch repair genes (mismatch repair genes (MLH1, MSH2, MSH6, PMS2, or EPCAM) also provide insights into the significance of DNA damage and microsatellite instability in urothelial cancer development. These mutations result in an autosomal dominant inheritance pattern that contribute to Lynch Syndrome, which is associated with an elevated risk of urothelial cancer of both the bladder and upper tract, colorectal cancer, endometrial cancer, and other malignancies.^23,24 Notably, patients with Lynch Syndrome do not exhibit a higher likelihood of upper tract urothelial cancer (UTUC) when compared to their risk of bladder cancer; however there is some evidence to suggest a higher proportion of DNA MMR gene mutations attributed to patients with primary UTUC.¹⁷

Environmental risk factors for UTUC to be further discussed in this article are linked to urothelial cancer and thought to be related to chronic exposure of nephrotoxic or carcinogenic chemicals within filtrate from systemic circulation (see ‘Risk Factors for Upper Tract Urothelial Cancer’). Patient-specific factors, such as age and comorbidities, may influence the ability to counteract these carcinogens, rendering some individuals more susceptible to disease progression and a poorer prognosis.

Figure 3: Various urothelial carcinoma presentations. In the top LEFT image, a pelvicalyceal UTUC is visualized during digital ureteroscopy (https://www.urologynews.uk.com/education/spot-tests/post/upper-urinary-tract-urothelial-cell-carcinoma). In the top RIGHT image, a ureteral UTUC is shown, which is multifocal but not causing obstruction (https://pubmed.ncbi.nlm.nih.gov/29182602/). Moving to the bottom LEFT image, we can see Carcinoma in Situ (CIS) in the bladder, indicated by the hyperemic area and 'denuded' epithelium (https://www.sciencedirect.com/science/article/abs/pii/B9780128099391000102). Finally, in the bottom RIGHT image, a bladder tumor is depicted, characterized by its papillary projection (https://www.cuh.nhs.uk/patient-information/bladder-tumour-resection/). These images provide valuable insights into different manifestations of urothelial carcinoma.

Risk Factors for Upper Tract Urothelial Cancer

History of Bladder Cancer

Individuals with a history of bladder cancer are at risk of developing upper tract urothelial carcinoma, either concurrently (synchronously) or subsequently (metachronously) to their bladder cancer diagnosis. The presence of multiple tumors, known as multifocality, significantly triples the risk of UTUC recurrence.

A flat malignant lesion, carcinoma in situ (CIS), is typically multifocal and significantly raises the risk of UTUC recurrence by 2 to 4 times. CIS can develop in various anatomical locations, including the bladder, upper urinary tract (UUT), prostatic ducts, and urethra. In the largest meta-analysis, involving 22 studies and over 13,000 patients, focused on predicting UTUC risk after a bladder cancer diagnosis, researchers discovered that factors linked to extended overall survival also correlated with the risk of urothelial carcinoma recurrence in the upper tract. Notably, the use of bladder-conserving therapy heightens the risk of UTUC. These factors include a history of CIS and low-grade tumors.²⁵ These factors contribute to an extended susceptibility period for upper tract recurrence, often referred to as the "opportunistic window."

Furthermore, following radical cystectomy for muscle-invasive bladder cancer (MIBC), approximately 3–5% of patients subsequently develop metachronous UTUC.²⁵ The use of stents in MIBC patients may raise the risk of UTUC through urinary reflux, prompting careful consideration and surveillance in patients who undergo conservative treatment.^26,27 In these cases, percutaneous nephrostomy tubes instead of internalized double J ureteral stents may offer a form of urinary diversion without introducing risk of UTUC. You may also find additional information in ‘Considerations for Patients with Primary Bladder Cancer’ section of this article.

Tobacco Exposure

Smoking tobacco is prominent risk factor for the development of urothelial cancer and increases the risk 2-7 times.²⁸ Individuals who are smokers at the time of diagnosis also face a higher risk of adverse outcomes, including disease recurrence, increased mortality rates, and a higher likelihood of intravesical recurrence after undergoing radical nephroureterectomy (RNU). Smoking cessation has been shown to be beneficial in improving cancer control in UTUC patients. Smoking cessation has been shown to be beneficial in improving cancer control in UTUC patients, though smoking cessation does not normalize the risk of UTUC to that of lifelong nonsmokers.

Aristolochic Acid Exposure and Pharmacologic Nephropathy

Aristolochic acid, a mutagen found in plants has been implicated in other cancer types such as renal cell carcinoma, hepatocellular carcinoma, and intrahepatic cholangiocarcinoma.²⁹ It has been linked to urothelial cancer and tubulointerstitial kidney disease in rural communities in Eastern Europe and Asia, posing several surgical and therapeutic challenges.³⁰ Aristolochic acid exposure can occur through environmental contamination of agricultural products by aristolochic plants³¹ or via the ingestion of aristolochic-based herbal remedies.³² It has been found that 10% of individuals exposed to this substance develop UTUC.³³  Aristolochic acid inflicts physical injury to the proximal tubules, leading to chronic tubulointerstitial disease; it’s role as a carcinogen has been linked to DNA damage.²⁹ Other risk factors for pharmacologic nephropathy that may be linked to UTUC, include analgesic overuse or abuse (phenacetin) and cyclophosphamide.

Family History of Lynch Syndrome

Patients with germline-confirmed Lynch Syndrome have increased risk of both UTUC and urothelial bladder cancer (EU Guideline, Section 3.4, Evidence  Strength: 2a). However, there is no recommended surveillance strategy in asymptomatic patients with Lynch syndrome.³⁴ Microhematuria and gross hematuria should prompt evaluation including imaging and cystoscopy.

If Lynch Syndrome is suspected, it is important to note personal history or familial history and corresponding age of diagnosis of the following Lynch-Spectrum cancers: colorectal, ovarian, endometrial, gastric, biliary, small bowel, pancreatic, prostate, skin, and brain cancer (UTUC AUA Guideline 7 – Evidence Strength: Expert Opinion). The use of Amsterdam criteria or Bethesda are screening tools for Lynch Syndrome, with variable utility (EU Guideline, Sect. 3.4 – Evidence Strength: Weak).³⁵

There is evidence to support universal somatic mutation testing of all UTUC tumors for microsatellite instability with immunohistochemistry (UTUC AUA Guideline 7 – Evidence Strength: B, Genetic/Familial High-Risk Assessment: Colon Cancer).³⁶ If a somatic mutation is found, germline testing for genes (MLH1, MSH2, MSH6, and PMS2 or EPCAM gene) is required to establish the diagnosis of Lynch syndrome. This may offer early linkage to genetic counseling and multidisciplinary disease management.

In sporadic UTUC cases, alongside those with a positive somatic mutation screen, germline testing for Lynch Syndrome should be considered in the following scenarios: individuals under 60 years of age, those with a family history of UTUC, individuals with two first-degree relatives affected by Lynch Spectrum Cancer, and those with a first-degree relative under the age of 50 diagnosed with Lynch Spectrum Cancer.³⁷

Additional Documented Exposures

The published evidence supporting a causative role for these factors is relatively weak. For instance, arsenic in drinking water has been tentatively linked to an elevated risk of UTUC in certain regions like Taiwan and Chile.³⁰ Additionally, alcohol consumption has shown an association with UTUC development, particularly in a substantial case-control study where individuals who consume alcohol exhibited a significantly greater risk compared to non-drinkers. Notably, this risk appears to escalate with higher levels of alcohol intake, suggesting a dose-response relationship and some independence from tobacco use on multiple variable regression.³⁸

Figure 4: Risk Stratification Schemas by EAU (top) and AUA (bottom)

General Approach to UTUC Screening and Diagnosis

Patient Presentation

Currently, there are no universal screening guidelines for UTUC, which means that early detection relies on patient symptoms and clinical suspicion.

Similar to bladder cancer, gross or microscopic hematuria represents the most prevalent presenting symptom of UTUC, occurring up to 80% of cases.³⁹ Flank pain can be experienced in the event of acute obstruction from ureteral clotting in up to 30% of cases.⁴⁰ Tumor growth is more likely to contribute to hydronephrosis thank flank pain from acute obstruction. Notably, the presence of hydronephrosis, symptomatic or otherwise,  has some evidence to suggest that primary ureteral involvement has poor oncologic outcome, and that hydronephrosis can suggest high risk disease. ^20,21 The presence of systemic symptoms, such as anorexia, weight loss, malaise, fatigue, fever, night sweats, or cough, in individuals with suspected UTUC warrants metastatic workup.⁴⁰ Once a decision regarding RNU has been made, the procedure should be carried out within 3-4 months of diagnosis (EAU Guideline, Section 6.4, Evidence Strength: 3).^40–42

Upper Tract Urothelial Cancer Work Up

The workup for urothelial cancer diagnosis and staging requires a careful balance between the benefit of cancer detection and the potential physical and financial harm to the patient from unnecessary testing (Clinical Principle, AUA Guideline Statement 12). Standardized assessment of endoscopic and radiographic features plays a crucial role in clinical staging and risk assessment. This assessment aids in determining whether patients are at "low" or "high" risk for invasive disease based on findings from endoscopic, cytologic, pathologic, and radiographic evaluations prior to definitive treatment (AUA Guideline Statement 9 – Evidence Strength: B, AUA Guideline Statement 10 – Evidence Strength: B). (For more information, see AUA Guideline Statement 10 and Figure 4).

Figure 5: Radiograph and CT depiction of 'filling defects' corresponding to contrast delineating the passable lumen of the urinary tract. Source: https://ajronline.org/doi/full/10.2214/ajr.09.2577

1. CT and MRI Urography: Urography lets clinicians visualize the course of contrast along the urinary tract, and may be applied to x-ray, magnetic resonance imaging (MRI), and computed tomography (CT). Intravenous (IV) contrast agents take time to enter and opacify the upper tract lumen, which is why this is called ‘delayed phase’. The use of CT urography is preferred because it has been shown to be the most reliable (Figure 5) (EAU Guideline, Section 5.7 – Strong Recommendation).⁴³ MRI urography is useful when CT is contraindicated (EAU Guideline, Section 5.7 – Weak Recommendation). It is also important to note that other conditions, such as fibroepithelial polyps, inverted papilloma, and fibromas, can also cause upper tract masses and associated tissue-attenuation filling defects.

Initial suspicion of UTUC can benefit from a cystoscopy along with cross-sectional imaging of the upper tract, including delayed contrast images of the collecting system and ureter (Strong Recommendation; Evidence Level: Grade B, AUA Guideline Statement 1). This allows for visualization of both ureters simultaneously to guide laterality prior to  endoscopic evaluation (Expert Opinion, AUA Guideline Statement 6) and offer insight into local disease.

Diagnostic Objectives: Rule out radiopaque stone disease, assess tumor laterality and size (including tumor size >2 cm), diagnose hydronephrosis, examine patient variant upper tract anatomy, and evaluate regional, local lymph nodes as well as local tumor extension.

2. Cystoscopy and Flexible Ureteroscopy: Flexible ureteroscopy combined with cystoscopy are common approach for UTUC diagnosis and staging through direct visualization of the bladder, the ureter, renal pelvis, and collecting system (Figure 3). This enables the determination of tumor size, and multifocality. Flexible ureteroscopy is most useful when voided urine cytology or CT urography are equivocal for either diagnosis or risk stratification of UTUC (EAU Guideline, Section 5.7 – Strong Recommendation). Urethrocystoscopy also allows for detection of concurrent bladder cancer (EAU Guideline, Section 5.7 – Strong Recommendation).

It also provides an opportunity for selective cytology and biopsy from the upper tract to maximize cancer detection along the entire luminal urinary tract in select cases (Strong recommendation; Evidence Level: grade C, AUA Guideline Statement 2, EAU Guideline, Section 5.7 – Evidence level:  3). Diagnostic ureteroscopy is strongly recommended when imaging and urine cytology alone are inadequate for diagnosing or risk stratifying suspected UTUC patients (Figure 4).

In cases with ureteral strictures or difficult upper tract access, minimizing the risk of injury through gentle dilation techniques such as temporary stenting is advised (Expert Opinion, AUA Guideline Statement 4). During ureteroscopy, there’s no evidence to support the examination of a radiographically and clinically normal contralateral upper tract (Expert opinion, AUA Guideline Statement 6). 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, AUA Guideline Statement 3).

Diagnostic Objective: To differentiate UTUC from other upper tract conditions such as radiolucent stones, polyps, or other benign causes; obtain tissue biopsy for CIS and urothelial cancer; opportunity for selective washing of upper tract for pathology, offer diagnosis with definitive treatment for acute obstruction, evaluate patient anatomy such as strictures prior to surgery,

3. Retrograde Pyelogram: In cases where ureteroscopy is unsafe or not possible, selective upper tract washing or barbotage for cytology is recommended, followed by pyeloureterography when high-quality imaging is difficult (Conditional Recommendation; Evidence Level: Grade C; AUA Guideline Statement 5).

Diagnostic Objective: To delineate the upper urinary tract including presence of stricture or other intrinsic causes of ureteral obstruction.

4. Cytology: Cytology can be performed on bladder or upper tract barbotage and selective washes as well as with voided urine. Abnormal urine cytology may indicate high-grade UTUC when bladder cystoscopy is normal. When ureteroscopy is not feasible, selective upper tract washing or barbotage for cytology is suggested. When positive, selective cytology, along with biopsy, can provide valuable information, especially when no visible tumor is present.

Cytology, although less sensitive for UTUC than for bladder tumors, remains useful for the affected upper tract. In cases of confirmed UTUC, selective washings with positive cytology are associated with higher stage disease (Strong Recommendation; Evidence Level: Grade C; AUA Guideline Statement 2).

Diagnostic Objective: Evaluate for CIS in grossly normal appearing tissue on inspection endoscopy; select for cytology the upper tract versus total voided urine.

Figure 6: Example of positive urine cytology - high nucleus to cytoplasm ratio and dense nucleoli suggest urothelial cancer. Source: https://www.oncozine.com/study-shows-urine-based-liquid-biopsy-outperforms-urine-cytology-in-detecting-bladder-cancer/

5. Biopsy: Biopsy has its drawbacks including patient discomfort, invasive testing, and possible risk factor for intravesical recurrence, though it is unclear how this affects the natural history of disease progression.⁴⁴

When biopsy is performed, the tissue should undergo immunohistochemical (IHC) or microsatellite instability (MSI) testing (AUA Guideline Statement8, See ‘Risk Factors’ Section). It's important to note that biopsies are not ideal for assessing invasive disease, as they may not always provide full-thickness specimens of containing urothelium to the thin muscularis (see Figure 2) in the upper tract. However, even in instances of incomplete biopsy during ureteroscopy, histologic analysis may provide some idea of lymphovascular invasion at the lamina propria which happens in 20% of invasive and impacts survival.

Objective: Obtain MMR protein and microsatellite instability analysis, determine lymphovascular invasion, aid in diagnosing rare forms of non-urothelial cancer subtypes of the upper tract (<10% of cases).

6. Laboratory Testing: Routine laboratory studies, including serum creatinine, glomerular filtration rate estimates, liver function tests, alkaline phosphatase, and culture, help assess patient comorbidities impacting surgical planning. Additional tests like nuclear medicine renograms provide valuable information about chronic kidney disease, renal reserve, and anesthetic considerations (Expert Opinion, AUA Guideline Statement 11).

Kidney disease has multiple possible interactions with UTUC. Kidney disease can result from surgery, chronic mass-forming lesions leading to hydronephrosis, pre-existing medical renal conditions, or even UTUC predisposing factors that are shared with nephropathy (See Risk Factors Section). The emerging field of ‘nephro-oncology’ may offer perspective on treatment strategies for UTUC patients who are at risk of experiencing substantial declines in renal function and renal replacement therapy.

Objective: Determine baseline renal function, CKD and proteinuria staging, early linkage to nephrology and renal replacement therapy, evaluate liver disease, and rule out active infection

7. Imaging for Tumor Staging: Chest imaging with x-ray or CT is essential for evaluating metastatic disease. Bone scans are recommended when there is clinical suspicion of bone metastases. such as bone pain, elevated alkaline phosphatase, or radiographic concern for bone involvement on other imaging modalities.

Objective: Determine extent of metastatic disease for tumor staging; determine eligibility for definitive surgical management vs. systemic therapy (See Therapy Section)

8. Role of PET Imaging: 18F-Fluorodeoxyglucose (FDG PET) is a radiotracer with a glucose component. Cancer cells are metabolically active relying on glycolysis, and therefore may have preferential signal or ‘avidity’.⁴⁵ However, there can be false signal because, like IV contrast, FDG PET tracer can also opacify and mask ‘avid signal’ when its excreted through upper tract. Outside of the urinary tract, PET/CT can help detect metastases and clinically relevant nodes.⁴⁶

Objective: Alternative imaging for those who cannot receive iodinated contrast, determine metastatic disease and clinically relevant nodal disease

Figure 7: FDG PET avid signal corresponding to retroperitoneal lymph nodes (red arrow), lung metastasis (black arrow), and bone metastasis to spine (blue arrow) following nephroureterectomy for UTUC  Source: https://www.sciencedirect.com/science/article/pii/S0001299821001057#fig0006

Considerations for Patients with Primary Bladder Cancer

Various factors, including low-grade bladder cancer, multifocality, and CIS, can elevate the risk of metachronous UTUC development. This patient subset may have an existing 'field' disease and often experience longer survival, opportunistic cancer recurrence, and higher rates of conservative, bladder-sparing treatment. Therefore, these factors should be taken into account when determining the need for screening metachronous UTUC in the context of a bladder cancer diagnosis.

In a study involving 82 patients treated with BCG and subjected to regular upper tract imaging during years 1-3, a 13% incidence of asymptomatic UTUC was observed. In contrast, a series of 307 patients without routine imaging showed a higher incidence of 25%.^26,47 This indicates that cross-sectional imaging plays a protective role in monitoring patients for metachronous UTUC and evaluating bladder cancer recurrence. For individuals with bladder cancer opting for conservative management, it is recommended to undergo regular cystoscopy, urinary cytology, and annual cross-sectional imaging. Additionally, reducing the use of double J ureteral stents in bladder cancer patients can lower the risk of metachronous UTUC. In these cases, percutaneous nephrostomy tubes offer an alternative method of urinary diversion compared to internalized double J ureteral stents.

Future Directions: Biology and biomarkers

The diagnostic landscape for UTUC is evolving towards cost-effective care and enhanced urine-based non-invasive testing of urothelial cancer. Recent findings suggest that combining urine cytology and cross-sectional imaging may be adequate for the initial UTUC diagnosis, leading to a quicker detection of urothelial cancer and potentially eliminating the necessity for invasive biopsy, ureteroscopy, and upper tract sampling unless absolutely necessary. Moreover, if ureteroscopy and biopsy are deemed necessary, there is data supporting the simultaneous use of ablative therapies (such as laser) during the endoscopic diagnosis of UTUC in specific patient populations to avoid need for further invasive options.

Advanced molecular techniques, such as FISH, have shown promise in detecting urothelial cancer through a 'liquid biopsy' of voided urine. One study demonstrated encouraging results, including 100% sensitivity for Xpert Bladder, 93% for FISH, and 52% for cytology, along with high negative predictive values.⁴⁸ The development of DNA methylation assays, RNA panels, and cell-free DNA panels may enhance the current sensitivity of urine testing for diagnosing urothelial recurrence and for post-treatment follow-up. It is crucial to further assess these biomarker panels in clinical settings involving screening, evaluation, and surveillance.

Staging

The staging of UTUC has always provided a challenge to Radiologists, Urologists, and Pathologists. Compared to lower tract UC (bladder, urethra), the upper tract tends to be under graded and under staged. There are several reasons for this. First of all, the size of the samples are substantially smaller than the transurethral resection (TUR) samples that can be obtained of the lower tract. Radiographic assessment of the ureter is difficult due to small size and caliber, and thus assessment of more granular details, such as depth of invasion, is often not feasible. The image below demonstrates the size of specimens that are obtained via ureteroscopic biopsy.

Figure 8: TNM classification for Urothelial Cancer Staging

Grading of UTUC is similar to the lower tract, with low grade (LG) and high grade (HG) disease. The majority of upper tract tumors are urothelial cancers. The 2017 TNM classification for UTUC published by the WHO/ISUP is shown below, adapted from the European Association of Urology guidelines for UTUC.⁴⁹ Low grade tumors will often recur but are less likely to progress to more invasive or metastatic disease. High grade tumors can also recur, but also have a higher predilection for invasion into the deeper layers of kidney or ureter, and metastatic disease.

One unique characteristic of the AUA UTUC Guidelines is the risk categorization that allows clinicians to determine the likelihood of disease recurrence and progression, and thus guide treatment plans. Patients are divided into “Low-risk” and “High-risk”. The designation of high or low risk is based on grade of tumor, ipsilateral urine cytology, radiographic characteristics such as invasion and obstruction, endoscopy appearance (single versus multiple tumors; papillary versus sessile or flat), and involvement of the lower urinary tract. More aggressive disease is often associated with sessile rather than papillary appearance of the tumor, multiple tumors in the upper tract (i.e. “multifocality”), cancer involvement of other sites in the urinary tract (bladder, urethra, contralateral unit). The Presurgical Clinical Risk Categories from the AUA UTUC Guidelines are shown below.

Imaging can assist in the staging of UTUC, evaluating both local and distant ie metastatic disease. Given the challenges of adequate staging and grading with ureteroscopic biopsies, imaging can add additional useful information. On CT imaging, heterogeneous texture on contrast and noncontrast imaging can suggest higher risk disease. While it is intuitive to assume that hydronephrosis is associated with more aggressive disease, there has been some variability in the literature regarding this finding. (GL) CT is also useful to evaluate for enlarged regional and distant lymph nodes, which could suggest metastatic disease. Finally, CT is also utilized to evaluate for lung metastases or other sites of metastatic disease (liver in particular). MRI is helpful in patients who cannot receive intravenous contrast for CT. Positron Emission Tomography (PET) imaging is utilized by some in the staging of UTUC, though its role in management remains unclear as more data evolves. One series found the sensitivity to be 82% and the specificity 84% in regard to lymph node metastases in patients undergoing surgery.⁵⁰

Treatment Options for Localized and Advanced UTUC

The treatment of UTUC is dependent on many factors, including both patient and tumor characteristics. The overall health, medical comorbidities, and performance status of the patient should be considered, and while the Urologist should consider a guidelines-based approach to treatment, the “standard of care” is not always appropriate for every patient. Patients with UTUC are often older, with substantial comorbidities, and quality of life factors are also critical to consider and discuss with the patient, such as the need for multiple procedures, the likelihood of requiring renal replacement treatment in the future, and likelihood of cure.

Endoscopic Ablation

The ideal patient for endoscopic ablation is the patient presenting with low risk favorable UTUC (see Risk Stratification table for details regarding this patient population). This treatment modality is most often approached in a retrograde manner (ie ureteroscopy), but an antegrade approach with percutaneous access is also possible for certain tumor characteristics. The oncologic outcomes of patients in this risk category undergoing endoscopic treatment versus nephroureterectomy (NU) are similar. The appeal of endoscopic treatment is renal function preservation and avoidance of a major abdominal surgery in more comorbid patients. Mitomycin is a chemotherapeutic agent that is often utilized in the treatment of bladder cancer, either in the perioperative single instillation or postoperative adjuvant setting. It is challenging to instill a chemotherapeutic agent into the upper collecting system, as it will immediately egress, and dwell time is minimal.  Mitomycin containing reverse thermal gel has been used in this patient population, including in the chemo ablative setting, ie in patients with residual tumor that could not be fully ablated endoscopically. Endoscopic treatment can also be used in patients who fall outside of the low-risk favorable category, though larger tumors are associated with a higher risk of invasive disease, which can lead to treatment failure.

Endoscopic ablation, as mentioned previously, can be approached via a retrograde or antegrade route, ie ureteroscopically or with percutaneous access. The antegrade percutaneous approach can be particularly useful for larger tumors or in tumors that cannot be accessed in a retrograde manner (example: lower pole calyx with angulation of the lower pole infundibulum that does not permit ureteroscopic access). Urologists use a variety of techniques for tumor ablation, including electrocautery and lasers. As previously mentioned, there is a role for ablation of tumor utilizing mitomycin containing reverse thermal gel. When using an antegrade percutaneous approach, a resectoscope can be advanced into the collecting system for larger lesions.

Intravesical Therapies in the Perioperative Setting

Chemotherapy agents instilled into the bladder after resection of bladder tumors remain standard of care for certain bladder cancer populations (based on degree of resection, grade and volume of cancer). Similarly, a single perioperative instillation of chemotherapy into the bladder may reduce the risk of bladder cancer after instrumentation of UTUC.

Nephroureterectomy and Segmental Ureterectomy

Patients with high-risk disease, who are candidates for surgery, should be offered either nephroureterectomy (NU) or segmental ureterectomy (SU). Nephroureterectomy includes removal of the kidney, ureter, and a small portion of the bladder called the ‘bladder cuff’. The bladder cuff is at high risk of recurrence if left in situ. These surgeries can be approached via open, laparoscopic, or robotic techniques, and similar oncologic outcomes have been noted. The bladder cuff is excised with the ureter in continuity ie en bloc.

Segmental ureterectomy can be utilized for patients with isolated disease in the distal ureter. It is important in this patient population to rule out any proximal urothelial cancer, ie in the more proximal kidney and ureter. Similar to NU, the entire distal ureter including the bladder cuff should be excised. Once the distal ureterectomy is completed, there are a variety of reconstructive options available depending on the length of ureter that is excised. The most frequently utilized options include primary reimplant into the bladder, boari flap, and psoas hitch.

Lymph Node Dissection

Lymph node dissection (LND) is an important step in many urologic and non-urologic malignancies. It can add important staging information, which could impact adjuvant treatment offered to the patient. In some malignancies, LND can also offer improved cancer specific survival due to removal of micro metastatic disease in the lymph nodes. The data regarding the role of LND in UTUC is challenging to accrue and to interpret due to the heterogeneity of UTUC, the absence of defined LND templates, and small sample sizes. The AUA Guidelines recommend that Urologists consider performing LND at the time of surgery in patients with low-risk disease, but all patients undergoing surgery for high-risk disease should be offered LND. There is some evidence that LND improves cancer survival in patients with higher stage disease. The figure below depicts the typical lymph node drainage basins for various segments of the upper urinary tract.⁵¹ The LND recommended templates are based on these drainage patterns.

Figure 9: Lymph node template for urothelial cancer based on primary location

The minimal template for LND outlined in the AUA guidelines is described as follows:

• Pyelocaliceal system: lymph nodes of ipsilateral great vessels extending from renal hilum to inferior mesenteric artery
• Proximal two-thirds of the ureter: lymph nodes of ipsilateral great vessels extending from renal hilum to aortic bifurcation
• Distal one-third of the ureter: lymph nodes of ipsilateral pelvic drainage basin including at a minimum the external iliac and obturator lymph nodes.

Adjuvant Therapy

Recognizing that high risk UTUC is aggressive by nature and that there may be compromised renal function secondary to obstruction from the tumor, it is important to consider preoperative neoadjuvant chemotherapy. Improved postoperative outcomes have been demonstrated by several neoadjuvant trials of cisplatin-based chemotherapy prior to nephroureterectomy (130-133). Importantly, radical nephroureterectomy may decrease renal reserve impair the ability of patients to receive platinum-based chemotherapies after surgery. Recognizing that neoadjuvant chemotherapy may not be possible or that pathologic stage may be more advanced than clinical staging in UTUC patients, clinicians should offer adjuvant platinum-based chemotherapy to patients with pT2 or higher UTUC after surgery who did not receive neoadjuvant chemotherapy. (135) In patients who do not wish to receive or are ineligible to receive platinum-based chemotherapy, adjuvant nivolumab may be given. Nivolumab can also be administered in patients who receive neoadjuvant chemotherapy who have high risk features after surgical intervention.

Advanced/Metastatic Disease

In patients with metastatic UTUC, surgery should not be pursued as first line therapy. Oncologic outcomes in these patients are primarily determined by the patient’s response to systemic therapy. Upfront surgery has not been shown to improve survival and may in fact negatively impact outcomes by delaying or precluding the use of systemic therapies. In patients with clinical node-positive UTUC without metastases should also be treated initially with systemic chemotherapy. Surgery can be considered in these patients who respond to systemic therapy, however. In patients who have unresectable UTUC, it is important to consider a clinical trial or ensure optimized supportive care. Palliative care should be considered to provide symptom control or optimize renal function. Therapies such as radiation or endoscopic tumor ablation may improve patient quality of life, however, appropriate goal setting is necessary.

Survivorship

Given that UTUC patients are at risk for reduced renal function, clinicians should monitor renal function and consider a referral to nephrology in those with proteinuria, an eGFR less than 45 mL/min/1.73m², diabetes mellitus, or whenever the eGFR is expected to be less than 30 mL/min/1.73m² after surgery. Additionally, care teams should encourage patients to optimize their health by exercising, eating a health diet, and stopping smoking.

Evaluation for Tumor Recurrence

Surveillance is a critical part of UTUC patient management. Importantly, the surveillance regimen is tailored to the disease risk and the treatment modalities utilized.  In low-risk patients who underwent kidney sparing surgeries, cystoscopy, upper tract endoscopy and upper tract imaging are required. Patients with high-risk disease managed by kidney sparing surgeries also require cystoscopy, upper tract endoscopy and imaging as well as urine cytology at more frequent intervals than patients with low-risk UTUC.

Concluding Statements

UTUC patients require a multidisciplinary team approach to optimize overall care. Access to medical genetics specialists, nephrologists, and medical oncologists are required for the unique are rare nature of this disease. Clinical trials with close collaboration between medical oncologists and urologists are addressing key issues in multidisciplinary care.

Medical students, as members of the healthcare team, can improve increasing early detection of UTUC with thorough history-taking and a general understanding of key symptoms and risk factors, as well as through team collaboration.

They can also participate in advocacy to ensure that high value treatment is offered equitably in their communities. Lastly, the role of research in this field holds promise for those inclined to study this rare disease.

Additional Resources AUA Core Curriculum: For more content on upper tract carcinoma, please follow the link below to access the AUA Core Curriculum.  Access is free for AUA members and Medical Students qualify for a free AUA membership!  Learn more on our membership page. Upper Tract Neoplasms Patient Education: Check out this free patient resource from the Urology Care Foundation. Upper Tract Urethral Carcinoma (UTUC)

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Authors

2023
Jennifer Yates, MD
Shrewsbury, MA
Disclosures: Nothing to disclose

Marisa Clifton, MD
Baltimore, MD
Disclosures: Nothing to disclose

Maria Antony
Farmington, CT
Disclosures: Nothing to disclose