Upper Urinary Tract Urothelial Cell Carcinoma

6. PROGNOSIS

6.1. Prognostic factors

Many prognostic factors have been identified and can be used to risk-stratify patients in order to decide on the most appropriate local treatment (radical vs. kidney-sparing) and discuss peri-operative systemic therapy. Factors can be divided into patient-related factors and tumour-related factors.

6.1.1. Patient-related factors

6.1.1.1. Age and gender

Older age at the time of RNU is independently associated with decreased cancer-specific survival (CSS) [119,120]. Gender has no impact on prognosis of UTUC [121].

6.1.1.2. Ethnicity

A multicentre study of international patients from various academic centres did not show any difference in outcomes between races [122]. In contrast, U.S. population-based studies have indicated that African-American patients have worse outcomes than other ethnicities. The cause of this difference is unclear, possibly being related to access to care and/or biological patterns. Another study has demonstrated differences between Chinese and American patients at presentation in terms of risk factors, disease characteristics and predictors of adverse oncologic outcomes [21].

6.1.1.3. Genetic pre-disposition

Patients who test positive for Lynch syndrome, are significantly younger and exhibit a higher prevalence of UTUC with for ureteral location [123]. No impact on prognosis has been shown to date.

6.1.1.4. Tobacco consumption

Being a smoker at diagnosis increases the risk for disease recurrence, mortality [124,125] and intravesical recurrence after RNU [126]. Smoking cessation over ten years improves outcomes to the level of non-smokers [125,127].

6.1.1.5. Surgical delay

A delay between diagnosis of an invasive tumour and its removal may increase the risk of disease progression. Once a decision regarding RNU has been made, the procedure should be carried out within twelve weeks, whereas a treatment delay below four weeks has been suggested for the subgroup of patients with ureteral UTUC [128-132].

6.1.1.6. Other factors

High comorbidity and performance indices scores (e.g. American Society of Anesthesiologists [ASA], performance status [PS], and Charlson Comorbidity Index) are also associated with worse survival outcomes across disease stages [133-136].

A higher ASA score confers worse CSS after RNU [137], as does poor PS [138]. Obesity and higher body mass index adversely affect cancer-specific outcomes in patients treated with RNU [139], with potential differences between races [140]. Several blood-based biomarkers have been associated with locally-advanced disease and cancer-specific mortality such as high pre-treatment-derived neutrophil- lymphocyte ratio [141-144], low albumin [143-145], high C-reactive protein [143] or modified Glasgow score [146], high De Ritis ratio (aspartate transaminase/alanine transaminase) [147], altered renal function [143,148] and high fibrinogen [143,148].

6.1.2. Tumour-related factors

6.1.2.1. Tumour stage and grade

The main prognostic factors are tumour stage and grade [111,120,149,150]. Upper urinary tract UCs that invade the muscle have a poor prognosis. In a large Dutch series of UTUC, 5-year CSS was 86% for non- muscle-invasive tumours, 70% for muscle-invasive organ-confined tumours and 44% for locally-advanced tumours [18]. A contemporary SEER analysis of RNUs for high-risk disease showed that 5-year CSS was 86% for T1N0, 77% for T2N0, 63% for T3N0 and 39% for T4N0/T any N1–3 [151]. pT3 sub staging (pT3a vs. pT3b) might be relevant [152]; however, high quality validation is lacking.

6.1.2.2. Tumour location, multifocality, size and hydronephrosis

6.1.2.2.1. Multifocality

Approximately 7-42% of UTUC patients have been reported to have multifocal tumours [153-157]. Patients with multifocal tumours are more likely to harbour advanced tumour stage and a worse prognosis despite treatment with RNU [153-157]. However, multifocal tumours can also have a good prognosis and be present in the setting of otherwise low-risk UTUC.

It is important to note that the definition of multifocality varies among studies. Some studies consider the number of lesions [156], while others focus on tumour location (i.e., both renal pelvis and ureter) [153-155,157].

Taken together, tumour multifocality alone is insufficient for risk stratification, and a combination of factors is needed to determine whether kidney-sparing surgery is a safe option. Patients should be categorised as high-risk UTUC not only when tumour multifocality is present but when it is accompanied by high risk factors (see Figure 6.1).

6.1.2.2.2. Hydroureteronephrosis

Hydroureteronephrosis has been linked to advanced disease and poor prognosis in patients treated with RNU [92,158,159]. A recent meta-analysis of 22 studies involving 7,542 patients found pre-operative hydroureteronephrosis to be significantly associated with ureteral tumour location, advanced tumour stage, and lymph node metastasis [160]. In addition, pre-operative hydroureteronephrosis was independently associated with worse overall, cancer-specific, and disease-free survival, but not intravesical recurrence [160].

It is important to note that some low-risk UTUC patients may exhibit hydroureteronephrosis with for example a pTa low-grade tumour obstructing the ureter. Taken together, just like tumour multifocality, the presence of hydroureteronephrosis alone is insufficient for risk stratification, and a combination of factors is needed to determine whether kidney-sparing surgery is a safe option. Patients should be categorised as high-risk UTUC not only when pre-operative hydroureteronephrosis is present but if it is accompanied by other high risk factors (see Figure 6.1).

6.1.2.2.3. Tumour size

Increasing tumour size is linked to a higher risk of muscle-invasive and non-organ-confined disease in both ureteral and renal pelvis UTUC cases [161]. A recent meta-analysis of 32,292 patients confirmed that larger tumours are significantly associated with worse overall, cancer-specific, and disease-free survival, as well as intravesical recurrence [161]. In renal pelvis UTUC, where the median tumour size ranges from 3.5 to 4.0 cm, each 1 cm increase in tumour size elevates the risk of harbouring muscle-invasive disease at RNU by 1.25-fold [162]. A recent multi-institutional study with 932 patients suggested that a 2 cm tumour size serves as the optimal threshold for identifying high-risk patients (> pT2 UTUC) [163]. However, measuring tumour size lacks standardisation, leading to inter-assessor variability.

Taken together, just like tumour multifocality and hydroureteronephrosis, tumour size alone is insufficient for risk stratification, and a combination of factors is needed to determine whether kidney-sparing surgery is a safe option. Therefore, similar to tumour multifocality and hydroureteronephrosis, tumour size alone should not dictate therapeutic decisions. Patients should be categorised as high-risk UTUC not only when tumour size exceeds 2 cm but if it is accompanied by other high risk factors (see Figure 6.1).

6.1.2.3. Pathological subtypes

Pathological subtypes are associated with worse CSS and overall survival (OS) [72]. Most studied subtypes are micropapillary [75], squamous [164] and sarcomatoid [75], all of which are consistently associated with locally-advanced disease and worse outcome [73]. Patients harbouring pathological subtypes should be proposed RNU after a shared-decision process due to the higher risk of progression.

6.1.2.4. Lymph node involvement

Patients with nodal metastasis experience poor survival after surgery [165]. Lymph node density (cut-off 30%) and extranodal extension are powerful predictors of survival outcomes in N+ UTUC [166-168]. Lymph node dissection (LND) performed at the time of RNU allows for optimal tumour staging, although its curative role remains controversial [167,169-172].

6.1.2.5. Lymphovascular invasion

Lymphovascular invasion (LVI) is present in approximately 20% of invasive UTUCs and is an independent predictor of survival [173-175]. Lymphovascular invasion status should be specifically reported in the pathological reports of all UTUC specimens [176,177].

6.1.2.6. Surgical margins

Positive soft tissue surgical margin is associated with a higher risk of disease recurrence after RNU. Pathologists should look for and report positive margins at the level of ureteral transection, bladder cuff, and around the tumour [178].

6.1.2.7. Other pathological factors

Extensive tumour necrosis (> 10% of the tumour area) is an independent prognostic predictor in patients who undergo RNU [179]. Where neoadjuvant treatment was given, pathological downstaging is associated with better OS [180,181]. The architecture of UTUC, as determined from pathological examination of RNU specimens, is also a strong prognosticator with sessile growth pattern being associated with worse outcome [182-184]. Concomitant CIS in organ-confined UTUC and a history of bladder CIS are associated with a higher risk of recurrence and cancer-specific mortality [185,186]. Macroscopic infiltration or invasion of peri-pelvic adipose tissue confers a higher risk of disease recurrence after RNU compared to microscopic infiltration of renal parenchyma [71,187].

6.1.3. Molecular markers

Because of the rarity of UTUC, the main limitations of molecular studies are their retrospective design and, for most studies, small sample size. None of the investigated markers have been validated to support their introduction in daily clinical decision making [79,143].

6.2. Risk stratification for clinical decision making

As tumour stage is difficult to assess clinically in UTUC, it is useful to stratify patients according to the low- and high risk of progression in order to identify those who are likely to benefit from kidney-sparing treatment and those who should be treated by radical nephroureterectomy [188,189]. The factors to consider for the risk stratification are presented in Figure 6.1.

The level of evidence to consider individually size, multifocality and hydronephrosis as a surrogate for high-risk of progression remains low. Therefore, in the presence of low-grade disease associated with these factors, a shared decision-making process with the patient is important to discuss the therapeutic strategy (kidney-sparing strategy or RNU).

Pre-RNU models aiming at predicting which patient has > pT2 /non-organ-confined disease have been published [190-194]. Several risk stratification models have been assessed with the main aim to identify better patients eligible for kidney-sparing surgery [188,189,195-197].

Prognostic nomograms based on pre-operative factors and post-operative pathological characteristics are also available [169,192,198-203] and may be used when counselling patients regarding follow-up and administration of peri-operative chemotherapy. Nevertheless, despite a moderate to good discrimination accuracy, severe heterogeneity discourages its use in systematic ways.

Figure 6.1: Risk stratification of non-metastatic UTUC according to the risk of progression to a> pT2 /non-organ-confined diseaseCT = computed tomography; URS = ureteroscopy; UTUC = upper urinary tract urothelial carcinoma.
* All these factors need to be present.
**Any of these factors need to be present.
***In the presence of low-grade tumour these factors are not strong predictors of invasive disease.

6.3. Bladder recurrence

A meta-analysis of available data has identified significant predictors of bladder recurrence after RNU [22]. Three categories of predictors for increased risk of bladder recurrence were identified:

1. Patient-specific factors such as male gender, previous BC, smoking and pre-operative chronic kidney disease.
2. Tumour-specific factors such as positive pre-operative urinary cytology, tumour grade, ureteral location, multifocality, tumour diameter, invasive pT stage, and necrosis [204,205].
3. Treatment-specific factors such as laparoscopic approach, extravesical bladder cuff removal, and positive surgical margins [22].

In addition, the use of diagnostic URS has been associated with a higher risk of developing bladder recurrence after RNU [206,207]. Based on low-level evidence only, a single dose of intravesical chemotherapy after diagnostic/therapeutic ureteroscopy of non-metastatic UTUC has been suggested to lower the rate of intravesical recurrence, similarly to that after RNU [22].

6.4. Summary of evidence and recommendation for the prognosis of UTUC