Two11 98 99 Urothelial tumors of upper urinary tract and ureter UTUC

• Pelvis - most common
• Ureter - in ureter, 70% in distal ureter, 25% in mid ureter and 5% in proximal ureter - reflexion of downstream implantation

Note -  Upper urinary tract carcinomas comprise only 5% of the urothelial cancers.

Geographic area in Southeast Europe


Balkan nephropathy is observed as a familial not inherited condition related to the dietary exposure to aristocholic acid

In the 70s and 80s - usually older than bladder tumor cases 

<65 yrs - rule out Lynch syndrome (HNPCC) - Amsterdam criteria for Lynch syndrome. Patients with HNPCC have mutations in the DNA mismatch repair genes

• 80-90% sporadic 
• 10-20% - hereditary 

UTUC are associated with poor prognosis

• Note -
• -   UTUCs are twice as frequent in men as in women

Genetic - associated with Hereditary nonpolyposis colorectal carcinoma 

• External risk factors 
• - Aristocholic acid nephropathy 
• - Smoking - tobacco increases risk by 2.5 to 7 times,  60% to 70% reduction in the risk for UTUC with interruption of smoking for more than 10 years.
• - Coffee 
• - Analgesics - phenacetin, caffeine, codeine, 
• - Arsenic -  Blackfoot disease is related to chronic exposure to arsenic
• - Occupation - coal, tar 
• - Chronic inflammation, infection - associated with stones or obstruction

• Phenacetin was used as an analgesic and fever-reducing drug in both human and veterinary medicine for many years.
• Not used now 
• Causes nephropathy 
• Thickening of basement membrane is pathognomonic of analgesic abuse - codeine, acetaminophen, caffeine

• Environmental exposure - Arsenic, or Aristocholic acid 
• Analgesic abuse 
• Lynch syndrome

• After known bladder cancer
• - Upper tract recurrance 2-8%, in 70 months 
• - Urethral recurrance 2-8%

• Bladder recurrence after UTUC
• - 15-75% in 5 years (downstream seeding)
• - most recurrent in bladder cuff within 2 years 

Incidence of Bilateral UTUC - 3-5%, maybe up to 25% in CIS

Cystoscopy should always be done before RNU. If bladder mass if found, take biopsy always. If TURBT is done, pluck methods are contraindicated - high chance of tumor seeding

Bladder with two extravesical sites 

In male - Bladder  + both urinary tract or prostatic urethra with one urinary tract 

In female - Bladder + both urinary tracts

• Urothelial - 90% 
• Squamous - 0.7-7% 
• Adenocarcinoma - 1%

Squamous cell carcinoma has an incidence 5 times higher in the renal pelvis than in the ureter and has been associated with the abuse of analgesics and chronic inflammation.

Squamous cell carcinoma and adenocarcinoma, although rare in the upper tract, are usually associated with long-term obstruction, inflammation, and occasionally calculi.

The classification and morphology of UTUC and bladder carcinoma are similar. However, it is not possible to distinguish between non-invasive (PULMP and low- and high-grade papillary UC, CIS), and invasive carcinoma. This is in most cases due to the size of biopsy specimens that do not include deep tissue required for pathological staging. With UTUC. Histological grade is a surrogate for pathological stage, as it strongly correlates. 

• Ta
• - Non-invasive papillary carcinoma

• Tis
• - Carcinoma in situ

• T1
• - subepithelial connective tissue

• T2
• - muscularis

• T3 
• - Renal pelvis - beyond muscularis into peripelvic fat or renal parenchyma
• - Ureter - beyond muscularis into periureteric fat

• T4
• - adjacent organs or through the kidney into perinephric fat

• N1
• - single LN ≤ 2 cm  in greatest dimension

• N2
• - single LN> 2 cm  in greatest dimensions, or multiple lymph nodes

• M1
• - Distant metastasis

• Note 
• -   Patients with T3 tumors located in the renal pelvis have a better survival than those with T3 tumors located in the ureter. Of renal pelvic tumors, 50% are invasive at diagnosis.

• RCC is not grossly infiltrative except collecting duct and medullary RCC. Urothelial layers may even extend to collecting ducts raising the possibility that collecting duct renal cancers may be closely related to urothelial cancers.  UTUC is grossly infiltrative
• Clear cell RCC is more enhancing (>100), no filling defect in the collecting system 

Collecting duct carcinoma may share features of UTUC, may respond to cisplatin or gemcitabine based chemotherapy, rest RCC are resistant to chemotherapy

• Filling defects in UTUC - blood clot, fungus, sloughed papilla, bowel gas 
• Urothelial cancers -  average density of 46 HU and range between 10 and 70 HU
• Uric acid stones - 100HU

Use diagnostic ureteroscopy and biopsy if imaging and cytology are not sufficient for the diagnosis and/or risk-stratification of the tumour (Strong, EAU 2021)

URS should be reserved for diagnostic uncertainty, if kidney-sparing treatment is considered, or in patients with a solitary kidney. There is higher rate of intravesical recurrence in patients (particularly in case of renal pelvic tumor) who undego URS before RNU.

Ureteroscopy increases the diagnostic accuracy of excretory or retrograde urography alone from 75% to 85%–90%. 

There is risk of seeding, extravasation, dissemination - do ureteroscopy only if absolutely necessary.

Voided - Sensitivity is 20% in Grade I, 45% in Grade II and 75% in Grade III 

Ureteral catherization and saline washing - False negative 22-35% 

Brush Biopsy - 90% sensitive and 90% specific, complications include perforation and haemorrhage. Cup biopsy usually fail to obtain adequate tissue in the ureter. 

• Loop biopsies may include the lamina propria layer in 100% of the specimens. The respective figure for cup biopsy is 62%. 
• A significant problem with ureteroscopic biopsy is that grade may be accurate, but accurate staging can be extremely difficult. 

Obtain cytology before giving high osmolar contrast agent

Low risk - kidney sparing techniques can be used in low risk diseases 

• • Unifocal disease
• • Tumour size < 2 cm
• • Low-grade cytology
• • Low-grade URS biopsy
• • No invasive aspect on CTU-uro graphy

High Risk (any of the following) - 

• • Hydronephrosis
• • Tumour size > 2 cm
• • High-grade cytology
• • High-grade URS biopsy
• • Multifocal disease
• • Previous radical cystectomy for highgrade bladder cancer
• • Variant histology

• Note - 
• - tumor <2cm - low risk 
• - node <2cm - N1

• Perform radical nephroureterectomy (RNU) in patients with high-risk non-metastatic upper tract urothelial carcinoma (UTUC) (Strong, EAU 2021)
• Remove the bladder cuff in its entirety (Strong , EAU 2021)
• Perform a template-based lymphadenectomy in patients with muscle-invasive UTUC (Strong, EAU 2021)
• Offer post-operative systemic platinum-based chemotherapy to patients with muscleinvasive UTUC (Strong, EAU 2021)
• Deliver a post-operative bladder instillation of chemotherapy to lower the intravesical recurrence rate (Strong , EAU 2021)

The hilum is controlled before excessive manipulation of the kidney 

Ureter is ligated early to prevent migration of tumor fragments into the bladder 

An adrenalectomy is not indicated for patients undergoing a nephroureterectomy for upper tract tumors.

• Dissemination of Disease in UTUC occurs by 
• - lymphatic
• - hematogenous invasion
• - epithelial spread by seeding or direct extension

Epithelial spread occurs in both antegrade and retrograde manner. More common is the antegrade seeding, high incidence of recurrence in patients in whom a ureteral stump is left in situ after nephrectomy and incomplete ureterectomy

“Field-effect” theory - the propensity of urothelium to diffusely form unrelated de novo tumors as a result of exposure to a mutagenic environment. 


Complete removal of the distal ureter and bladder cuff offers superior oncologic outcomes to incomplete resection.

The risk of tumor recurrence in a remaining ureteral stump is 30% to 75%. Adequate cystoscopic surveillance of residual distal ureter stump after nephroureterectomy is virtually impossible, contributing to high rates of local recurrence.

Therefore the entire distal ureter, including the intramural portion and the ureteral orifice, must be removed.

Five different approaches: 

Traditional open distal ureterectomy - transvesical or extravesical or combined - for adequate access to the entire intramural ureter, the lateral pedicle of the bladder (obliterated artery; superior, middle, and inferior vesical arteries) must be ligated and divided.  A cuff of bladder is removed en bloc with the ureter by applying a clamp to bladder wall and excising the full intramural portion of the ureter, taking care to stay away from the contralateral ureteral orifice. 

In the transvesical approach, anterior cystotomy is made, and intravesical dissection of the ureter is performed, including a traditional 1-cm mucosal cuff around the orifice. A wider margin can be taken if a gross tumor is seen protruding from the orifice, and if an invasive intramural tumor is suspected, an en bloc partial cystectomy may be required to ensure negative margins.

Transvesical ligation and detachment techniques - two 5mm trocars from the suprapubic region, incise with collin knife, ligate with endoloop, continuous suction to minimize extravasation of fluid 

Transurethral resection of ureteric orifice - Pluck or Abercrombie technique, The entire orifice and intramural ureter are resected transurethrally until the extravesical fat is seen,  concern about tumor seeding, this technique is abandoned

Intussusception (Stripping technique) - It is contraindicated in the presence of ureteral tumors. At the beginning of the procedure, a ureteral catheter is placed in the ureter, and nephrectomy is carried out as usual. The distal ureter is isolated extravesically, and a tie is placed around it, securing the catheter to the ureter. After the nephrectomy portion is completed, the ureter is transected between ties, and the bladder cuff is incised cystoscopically using a Collins knife. Pulling on the ureteral catheter everts the distal ureter inside the bladder. The intussuscepted ureter is then removed by traction out of the urethra. The edges of the bladder mucosa can be fulgurated. The concerns with this technique include exposure of bladder urothelium to ureteral mucosa with extensive manipulation of ureter and the potential for incomplete intramural ureter excision. In addition, the failure rate of 18.7% has been described, in which there was disruption of the ureter during manipulation and the need for an additional surgical incision

• Total laparoscopic technique
• Procedure - Initially, cystoscopy may be performed and the ureteral orifice cauterized, which may be preceded by placement of a ureteral catheter and incision of intramural tunnel at the 12 o'clock position. The nephrectomy portion is performed as usual, and the distal ureter is traced to the detrusor muscle. The ureteral dissection is carried down to the bladder. The detrusor muscle is split and the ureter retracted in antegrade direction. The endovascular stapler is then used to place a staple line as distally as possible. The fulguration mark helps serve as an identifier of bladder cuff.
• Advantages - avoids incision into the urinary tract, and in experienced hands the operative time is reduced.
• Disadvantages - potential for leaving ureter mucosa within the staple line and inability for the pathologist to evaluate the distal margin because of the presence of staples, higher risk of positive margins, which in this disease is associated with significantly reduced survival 
• Contraindications - presence of distal ureteral tumors.

A single post-operative dose of intravesical chemotherapy (mitomycin C, pirarubicin) 2-10 days after surgery reduces the risk of bladder tumor recurrence within the first years post-RNU. 

Deliver a post-operative bladder instillation of chemotherapy to lower the intravesical recurrence rate. Strong. EAU 2020

Instillation of mitomycin - Within 3 to 7 days after nephroureterectomy and with the catheter still in place from surgery, patients undergo cystogram to confirm absence of leakage from the site of bladder cuff resection. If the scan is negative, a single dose of mitomycin is instilled into the bladder, and the catheter is clamped, allowing a dwell time of at least 1 and up to 2 hours.

• Instillation of gemcitabine at the time of nephroureterectomy. The rationale for this change is the following:
• (1) it does not require the patient to return for cystogram and an additional clinic visit;
• (2) it allows for possible earlier removal of the urinary catheter after surgery and before discharge;
• (3) it would preclude situations when leakage at the site of the bladder cuff would result in treatment being canceled; and
• (4) it is given, theoretically, at the most effective time period when seeding is thought to occur.

In cases of intraoperative chemotherapy instillation, a 2- or 3-way urinary catheter is placed either on the sterile field or sterilely off the field, and the bladder is drained, after which the chemotherapy can be administered intravesically before the surgery is started. A clamp is placed on the outflow (also on inflow if using a 3-way catheter; we do this when the catheter is placed off the sterile field to allow the nursing circulator to easily irrigate the bladder using attached irrigation tubing). The anesthesia team is requested to minimize intravenous fluid administration because the bladder will be clamped for 1 to 2 hours. After surgery has started, once the ureter is clipped below the level of the tumor and after at least 1 and up to 2 hours of dwell time, the circulator can remove the clamp(s) and drain the bladder.

Lymphadenectomy has prognostic and possible therapeutic value in patients with T2 to T4 disease.

• Limited - 
• - For renal pelvis and proximal ureter - ipsilateral hilar and adjacent paraaortic or paracaval 
• - For Distal ureter - pelvic nodes 

• Extended lymphadenectomy template -
• - For tumors of renal pelvis this includes ipsilateral hilar, paracaval, retrocaval, and interaortocaval nodes up to the level of inferior mesenteric artery for right-sided tumors, and ipsilateral hilar and para-aortic up to the level of inferior mesenteric artery for left-sided tumors.
• - For tumors of the upper two-thirds of the ureter (above crossing of inferior mesenteric artery to the common iliac artery), the template is similar, but the distal border of dissection is extended to the level of aortic bifurcation.
• - For tumors of the lower one-third of the ureter, these include ipsilateral obturator, internal, external and common iliac,
• and presacral packets.

Perform a template-based lymphadenectomy in patients with muscle-invasive UTUC. (Strong, EAU 2020)

• - Endoscopic ablation - - Ureteroscopic appraoch and percutaneous approach
• - Ureteral resection
• - Partial nephrectomy

Instillation of BCG or mitomycin C in the upper urinary tract via percutaneous nephrostomy after complete tumour eradication. 

• Offer kidney-sparing management as primary treatment option to patients with low-risk tumours (Strong, EAU 2021)
• Offer kidney-sparing management (distal ureterectomy) to patients with high-risk tumours limited to the distal ureter (Weak, EAU 2021)
• Offer kidney-sparing management to patients with solitary kidney and/or impaired renal function, providing that it will not compromise survival. This decision will have to be made on a case-by-case basis in consultation with the patient (Strong, EAU 2021)

In UTUC, the margin of resection is often invisible, use of intraoperative USG is always necessary

• Excision of the ureter with 
• - uretero-ureterostomy - Ureter is ligated 1-2 cm above and below the suspected tumor margin
• - UCN - Refluxing UCN is done in UTUC that make surveillance of upper tract easier
• - Ileal ureter replacement
• - Autotransplantation

• Segmental ureterectomy is offered for low-grade, non–muscle-invasive disease of the proximal ureter or mid-ureter that is not amenable to complete ablation by endoscopic means because of tumor size or multiplicity.
• Distal ureterectomy and neocystostomy may be offered for lowgrade, low-stage, or in select cases, high-grade, locally invasive tumors of the distal ureter when renal preservation is necessary.

Large tumors, kidney tumors - antegrade, in percutaneous approach, we can use larger instruments 

Small tumors in ureter - retrograde

In ureteroscopic resection, only the intraluminal tumor is resected and no attempt is made to resect deep (beyond lamina propria). In pelvis tumor, deep resection with standard resectoscope  can be done

• In ureterosopic apporach
• - Biopsy forceps 
• - Flat wire basket 
• - Ureteroscopic resectoscope 

Base is ablated with laser or bugbee after enough tissue sampling

• In percutaneous approach 
• - Biopsy forcep with bugbee
• - Standard resectoscope 
• - Standard nephroscope and Holmium laser 
• - Flexible cystoscope and Holmium laser

Regardless of approach, a nephrostomy tube is left in place. This access can be used for second-look follow-up  nephroscopy to ensure complete tumor removal. Nephroureterectomy is indicated if the pathologic examination shows high-grade or invasive disease. Second-Look Nephroscopy. Follow-up nephroscopy is performed 4 to 14 days later to allow adequate healing. The tumor resection site is identified, and any residual tumor is removed. If no tumor is identified, the base should be sampled and treated by cautery or the Nd:YAG laser (15 to 20 W and 3-second exposures). The nephrostomy tube can be removed several days later if all tumors have been removed.

The diagnosis of isolated CIS of the upper urinary tracts is a difficult one because of the inability to evaluate the urothelium of the upper tracts with adequate tissue samples. In most cases the diagnosis is one of exclusion, wherein there is a persistent positive selective cytology in the absence of any ureteroscopic and radiographic findings.

• The presence of CIS increases the incidence of bilateral and multifocal disease. The bilateral disease has an overall incidence of 3% to 5% of UTUC cases. The presence of CIS increases this incidence to 25%. Patients with CIS have a higher risk for subsequent panurothelial disease since there is a high probability for multifocal disease. 
• In most cases the diagnosis is one of exclusion wherein there is a persistent positive selective cytology in the absence of any ureteroscopic or radiographic findings. 
• No surgical intervention in the absence of any histologic, radiographic, or endoscopic findings owing to the limitations of cytology alone with false-positive results and the high risk for bilateral disease in the future.
• Nephroureterectomy if one can confirm radiographically or endoscopically

After organ sparing - instillation of chemo/immunotherapeutic agents (nephrostomy or retrograde instillation), brachytherapy 

After complete excision -  chemotherapy, radiation therapy (there is lack of evidence to support the benefit of radiation in adjuvant/neoadjuvant setting)

Limitation of using adjuvant chemotherapy for advanced UTUC remains the limited ability to deliver full dose cisplatin-based regimen after RNU, given that this surgical procedure is likely to impact renal function.

Offer peri-operative chemotherapy to patients with muscle-invasive UTUC. Weak EAU 2020

Peri-Operative chemotherapy versus sUrveillance in upper Tract urothelial cancer

Presented after the trial was stopped early as a result of meeting predefined efficacy criteria. 

Patients with high risk of recurrence (pT2-4 N0-3 M0). 

Patients in the adjuvant arm received gemcitabine and cisplatin if postoperative creatinine clearance was more than 50 and gemcitabine carboplatin if clearance was 30 to 49. At a median follow-up of 17.6 months, 2-year disease-free survival was 51% for surveillance and 70% for chemotherapy. 

Gemcitabine–platinum combination chemotherapy initiated within 90 days after nephroureterectomy significantly improved disease-free survival in patients with locally advanced UTUC. 

POUT trial established  adjuvant chemotherapy as a standard for patients with high risk of recurrence after nephroureterectomy.

• When there is evidence of regional lymph node metastases, initial chemotherapy should be given as the primary therapy, and surgery should be withheld until a good —ideally a complete—radiographic response is seen.
• Generally, two additional cycles after maximal response are given (usually a total of 6 cycles). At that time, consolidative surgery that includes lymphadenectomy can be offered, similar to the paradigm for bladder urothelial carcinoma.

EAU 2021 - 

RNU  as a palliative treatment to symptomatic patients with resectable locally advanced tumours. Weak

• First-line treatment for cisplatin-eligible patients
• Use cisplatin-containing combination chemotherapy with GC, MVAC, preferably with G-CSF, HD-MVAC with G-CSF or PCG. Strong
• Do not offer carboplatin and non-platinum combination chemotherapy. Strong

• First-line treatment in patients unfit for cisplatin
• CPI  pembrolizumab or atezolizumab depending on PD-L1 status. Weak
• Offer carboplatin combination chemotherapy if PD-L1 is negative. Strong

• Second-line treatment
• CPI , pembrolizumab or atezolizumab to patients with disease progression during or after platinum-based combination chemotherapy for metastatic disease. Strong

Vinflunine as third- or subsequent-treatment line. Strong

• After radical nephroureterectomy
• Low-risk tumors - cystoscopy at three months. If negative, perform subsequent cystoscopy nine months later and then yearly, for five years. Weak
• High-risk tumors - Perform cystoscopy and urinary cytology at three months. If negative, repeat subsequent cystoscopy and cytology every three months for a period of two years, and every six months thereafter until five years, and then yearly. Weak
• Perform computed tomography (CT) urography and chest CT every six months for two years, and then yearly. Weak

• After kidney-sparing management
• Low-risk tumors - Perform cystoscopy and CT urography at three and six months, and then yearly for five years. Weak. 
• Perform ureteroscopy (URS) at three months. Weak
• High-risk tumors - Perform cystoscopy, urinary cytology, CT urography, and chest CT at three and six months, and then yearly. Weak. 
• Perform URS and urinary cytology in situ at three and six months. Weak

• Lymphatic drainage of ureters follows the pattern similar to the arterial blood supply 
• - upper part of each ureter drains to the lumbar nodes 
• - middle part of ureter drains to lymph nodes associated with the common iliac vessels 
• - inferior part of each ureter drains to lymph nodes associated with the external and internal iliac vessels