OBJECTIVE: To present the EAU guidelines for urothelial carcinoma of the urinary tract (UUT-UCC) to guide clinicians in their daily practice.
EVIDENCE ACQUISITION: The reviewed literature was obtained through a systematic Medline search with the following keywords: urothelial tumor, urothelial carcinoma, upper urinary tract, carcinoma, metastatic epithelium, renal pelvis, ureter, bladder cancer, chemotherapy, nephroureterectomy, adjuvant therapy, neoadjuvant therapy, recurrence, risk factors, survival.
INTEGRATION OF EVIDENCE: Most studies remain retrospective analyses. Recommendations for diagnosis, radical and conservative treatment are given, as well as a discussion of factors influencing prognosis, and recommended follow-up protocols based on different treatment options.
CONCLUSION: The above guidelines provide information on individualized diagnosis and treatment based on the latest research findings. Introduction
Based on a systematic literature search, the EAU Upper Urinary Tract Uroepithelial Carcinoma (UUT-UCC) Guidelines Working Group has prepared a new version of the 2011 guidelines.
Evidence acquisition
A combined multi-keyword search was performed using Medline for the treatment of uroepithelial malignancies and UUT-UCC using the following keywords: urothelial tumor, uroepithelial carcinoma, upper urinary tract, carcinoma, metastatic epithelium, renal pelvis, ureter, bladder cancer, chemotherapy, nephroureterectomy, adjuvant therapy, neoadjuvant therapy, recurrence, risk factors, and survival. Most of the literature on UUT-UCC, including some large multicenter studies, is retrospective. Evidence integration epidemiology
Urothelial carcinoma of the upper urinary tract is relatively uncommon, accounting for only 5-10% of UUTs. The annual incidence of UUT-UCC in Western countries is estimated to be 1-2 per 100,000 people. In 8-13% of cases, there is concurrent bladder cancer. 30-51% of cases after UUT-UCC present with bladder recurrence and 2-6% of cases present with contralateral upper urinary tract tumors.
UUT-UCC is already an invasive cancer at the time of diagnosis, compared to 15% of bladder cancers. the high incidence of UUT-UCC is at the age of 70 and 80 years, and the incidence in men is more than 3 times that of women. There is a familial aggregation of some UUT-UUC with hereditary non-adenomatous colorectal cancer (HNPCC).
Risk factors
Many environmental factors are associated with the development of UUT-UCC. Smoking and occupational exposure are the main exogenous risk factors. Smokers are 2.5-7 times more likely to develop UUT-UCC, and occupational exposure to aniline substances is another risk factor.
Although the incidence of Balkan nephropathy is decreasing yearly, some studies have proposed that aristolochic acid and herbal medicines are associated with the development of this disease. The presence of genetic diversity allows for differences in individual susceptibility. Only one of these specific genes has been reported, an allele named SULT1A1*2 that decreases sulfotransferase activity and thus is able to increase the risk of UUT-UCC. The development of epithelial carcinoma of the upper urinary tract is also associated with chronic inflammation and infection caused by stones.
Histology and classification
Histologic typing
More than 95% of uroepithelial cancers originate in the uroepithelium, leading to UUT-UCC and bladder cancer. Tumor morphologic variants have been identified in UUT-UCC, and such variants are more common in uroepithelial tumors of the kidney. These variants usually occur in high-grade tumors and in these tumors are usually accompanied by a variant condition such as: micropapillary, clear cell, neuroendocrine, and lymphoepithelial. Upper urinary tract tumors of non-uroepithelial origin are very rare.
Classification
They can be classified as non-invasive papillary tumors (papillary uroepithelial tumors of low malignant potential, low-grade papillary uroepithelial carcinoma, high-grade papillary uroepithelial carcinoma), flat type (carcinoma in situ) and invasive tumors.
Staging
Table 1 represents the 2009 TMN staging of the International Union Against Cancer.
Table 1 UUT-UCC TNM staging (2009 version)
Primary tumor
Primary tumor could not be determined
No evidence of primary tumor
Non-invasive papillary carcinoma
Carcinoma in situ
Tumor infiltrates into subepithelial connective tissue
Tumor invades the muscular layer
(renal pelvis) tumor infiltrates beyond the muscular layer and infiltrates the peripelvic fat or renal parenchyma
(Ureter) Tumor infiltrates beyond the muscular layer and infiltrates the fatty tissue around the ureter
Tumor infiltrates adjacent organs or penetrates the kidney to infiltrate the perinephric fat
Regional lymph nodes
Local lymph nodes cannot be identified
No local lymph node metastasis
Single lymph node metastasis with a maximum diameter ≤
Single lymph node metastasis with a maximum diameter of 2-5 cm, or multiple lymph node metastasis with a maximum diameter ≤
Lymph node metastasis, maximum diameter
Distant metastasis
No distant metastasis can be determined
No distant metastasis
With distant metastasis
Tumor grading
The grading system classifies non-invasive tumors into the following three groups: papillary uroepithelial tumors of low malignant potential, low-grade uroepithelial carcinoma, and high-grade uroepithelial carcinoma. Tumors of low-grade malignant potential are virtually absent in the upper urinary tract.
Symptoms
The most common symptom is visual or microscopic hematuria (70-80%). Low back pain may be present in 20-40% of patients and a lumbar mass may be present in 10-20% of patients.
Diagnosis
Imaging
Multi-helical CT urography Enhanced CT urography (MDCTU) has replaced intravenous urography as the gold standard for understanding the condition of the upper urinary tract.
Magnetic resonance imaging. MRI urograms are indicated for patients who are unable to undergo MDCTU.
Cystoscopy and urine cytology
Positive urine cytology is highly suggestive for the diagnosis of UUT-UUC when cystoscopy is normal and can exclude carcinoma in situ of the bladder or posterior urethra. Positive cytology is mostly indicative of muscle invasion or non-organ confined disease, which is significant for tumor staging.
Examination of molecular abnormalities by fluorescence in situ hybridization (FISH) techniques in UCC screening is becoming more common, but only a preliminary result is currently available
Diagnostic ureteroscopy
Ureteroscopy is a better screening modality for diagnosing UUT-UCC. The flexible, bendable ureteroscope allows visualization of the general shape of the ureter and access to the renal pelvis in 95% of cases. Soft ureteroscopy is particularly important in patients with uncertain diagnosis, conservative treatment considerations and isolated kidneys.
Recommended grade
Urine cytology
Cystoscopy has ruled out concomitant bladder cancer
Spiral CT urinary tract imaging
Prognostic factors
UUT-UCC that invades the muscularis usually has a poor prognosis. pT2/T3 patients have a 5-year survival rate of less than 50% and pT4 patients less than 10%. This section briefly describes the currently identified prognostic factors.
Tumor staging and grading
According to the latest classification, tumor stage and grade are the most important prognostic factors.
Age and gender
The impact of gender on UUT-UCC mortality has recently remained controversial, but it is no longer considered an independent prognostic influence. In contrast, patient age is still considered an independent prognostic indicator, as higher age at RNU is associated with lower tumor-specific survival rates.
Tumor location
Recent studies have shown that the location of the tumor in the upper urinary tract is no longer considered a prognostic indicator.
Vascular lymphatic invasion
Pulmonary lymphatic invasion is present in 20% of patients with UUT-UCC and is considered to be an independent prognostic factor. However, vasculo-lymphatic invasion is only suggestive of prognosis in patients with negative lymph nodes.
Other factors
Extensive tumor necrosis is an independent predictor of clinical prognosis in patients after RNU surgery. Extensive tumor necrosis is defined as the presence of necrosis in more than 10% of the tumor area.
The tumor architecture (with/without a tip) correlates with the prognosis of patients after RNU surgery. Tilless growth tends to suggest a poorer prognosis.
Carcinoma in situ in organ-confined UUT-UCC often implies a high risk of recurrence and high cancer-related mortality, and carcinoma in situ is an independent predictor of poorer prognosis in organ-confined disease.
Molecular markers
Microsatellite instability (MSIs) is an independent molecular marker that can indicate tumor prognosis. e-calherin, along with hypoxia-inducible factor (HIF)-1α and telomerase RNA components, has been shown to be an independent predictor of prognosis. As of today, however, no molecular marker has been widely validated to support its use as a reference standard for clinical decision making.
Treatment
Limited disease
Radical total nephroureteral ureterectomy (RNU) Radical total nephroureterectomy with cystic sleeve resection is the gold standard of treatment for UUT-UCC in all locations. The surgical procedure must strictly adhere to the anaplastic principle, and the urinary tract must not be incised intraoperatively to prevent tumor implantation.
Several other techniques that simplify the removal of the distal ureter have also been revisited: stripping, transurethral wall segmental ureter resection, and decortication. With the exception of ureteral stripping, the results of several other techniques are comparable to those of cystic sleeve resection. Disease progression may occur with a time from diagnosis to surgery of more than 45 days.
Lymph node dissection at the time is of therapeutic interest and contributes to accurate staging. Lymph node dissection is not necessary for patients with Ta-T1, as the reported positive rate of lymph node dissection in patients with T1 stage is 2.2% compared to 16% in patients with T2-4 stage. In addition, the authors found that the incidence of positive lymph nodes continued to increase with increasing T stage.
The safety of laparoscopic RNU has not been well documented. Recent data have tended to conclude that laparoscopy achieves the same tumor control as open surgery. Infiltrative, large volume (T3/T4 and/or N+/M+) or multifocal tumors are generally contraindications to laparoscopic RNU.
Recommended grade
Imaging suggestive of infiltrative disease
Urine cytology suggestive of high-grade tumor
Multifocal (in patients with non-isolated kidney)
Techniques to perform radical nephro-ureterectomy
Open versus laparoscopic approach can achieve the same results
Cuff resection of the bladder is mandatory
Techniques for cystic cuff resection other than dissection are acceptable
Lymph node dissection recommended for infiltrative disease
Conservative treatment Conservative treatment of patients with low-risk UUT-UCC preserves renal function and avoids the complications associated with open radical surgery. Some patients are forced to use conservative treatment due to their condition (renal insufficiency, isolated kidney), and it can also be performed optionally in low-stage, low-grade cases (normal contralateral renal function).
Ureteroscopy Endoscopic ablation can be performed in highly selective patients when the following conditions are present.
A bendable soft ureteroscope (not a rigid one), laser emitter, and biopsy forceps must be available; the patient should be informed of the need for close postoperative follow-up; and radical resection is still recommended to the patient.
Partial ureterectomy
Partial ureterectomy is more suitable for low- or high-risk tumors of the distal ureter; however, it is important to ensure that the tumor surrounding tissue is not invaded. For partial ureterectomy of the iliac and lumbar segments, the success rate is significantly lower than that of the distal ureter.
Open resection of pelvic and calyx tumors is no longer performed. Removal of pelvic and calyx tumors alone is technically more difficult and has a higher rate of tumor recurrence than partial ureteral resection.
For low-grade or non-invasive UUT-UCC located in the renal pelvis, a percutaneous approach can be considered, mainly for low-grade tumors of the inferior calyces that cannot be treated by ureteroscopy.
Local adjuvant treatment of UUT-UCC or CIS is technically feasible after conservative treatment (complete tumor elimination) with local adjuvant therapy via special nephrostomy tubes or ureteral stent tubes infused with BCG or mitomycin C. Its intermediate treatment results are similar to those of bladder cancer, with no long-term results available.
Indications for conservative treatment
Recommended grade
Single lesion
Small tumors
Low-grade tumor (cytology or biopsy)
No infiltrative manifestations
Able to be followed closely
Techniques for conservative treatment
Laser should be used for endoscopic treatment
Soft ureteroscopy is preferred over rigid
Open partial ureterectomy is an option for pelvic ureteral tumors
Percutaneous puncture route for low-grade, small calyceal tumors that cannot be treated by ureteroscopy
Progressive disease
full-length ureterectomy. Although available as a palliative treatment option, it does not benefit patients who have developed metastases.
Chemotherapy Since UUT-UCC is a uroepithelial tumor along with bladder cancer, platinum-based chemotherapy regimens are expected to produce similar results to bladder cancer. A number of platinum-based chemotherapy regimens have been used in the clinic.
Only one study has reported the effect of neoadjuvant chemotherapy, unlike its performance in bladder cancer, and initial data confirm that the regimen is effective in UUT-UCC, but further survival data and follow-up results are needed to verify this.
Patients receiving adjuvant chemotherapy can have a recurrence-free rate of up to 50%, but its impact on survival is minimal. Not all patients are suitable for adjuvant chemotherapy due to post-radical surgery comorbidities and impaired renal function. Due to insufficient current data, it is not possible to provide any recommendation.
Radiotherapy Adjuvant radiotherapy may improve local control of the disease. When administered in conjunction with platinum-based chemotherapy, it can prolong disease-free survival and overall survival. Radiotherapy alone or in combination with chemotherapy is now rarely used as conservative treatment of tumors.
Follow-up
Rigorous postoperative follow-up includes: all cases must be checked for the presence of bladder cancer and tested for local recurrence and distant metastases (invasive cases).
After radical total nephroureterectomy, follow-up is at least 5 years
Recommended grade
Non-invasive tumor
Cystoscopy/urine cytology: at 3 months postoperatively and annually thereafter
Spiral CT urogram: once a year
Infiltrative tumors
Cystoscopy/urine cytology: 3 months post-operative and annually thereafter
Spiral CT urogram: once every 6 months for 2 years, then annually thereafter
After conservative treatment, at least 5 years of follow-up
Urine cytology and spiral CT urography: 3 months and 6 months after surgery, and annually thereafter
Cystoscopy, ureteroscopy, cytology at the lesion: 3 months and 6 months after surgery, then once every 6 months for 2 years, then annually thereafter
The above guidelines provide information for individualized diagnosis and treatment based on the latest research findings. The clinician must decide the appropriate treatment for the patient based on the patient’s renal function, comorbidities, tumor location, tumor stage and grading, and molecular markers.