T—Primary tumor
TX
Primary tumor cannot be assessed
T0
No evidence of primary tumor
Ta
Noninvasive papillary carcinoma
Tis
Carcinoma in situ
T1
Tumor invades subepithelial connective tissue
T2
Tumor invades muscularis
T3
(Renal pelvis) Tumor invades beyond muscularis into peripelvic fat or renal parenchyma
(Ureter) Tumor invades beyond muscularis into periureteral fat
T4
Tumor invades adjacent organs or through the kidney into perinephric fat
N—Regional lymph nodes | |
NX | Regional lymph nodes cannot be assessed |
N0 | No regional lymph node metastasis |
N1 | Metastasis in a single lymph node 2 cm or less in greatest dimension |
N2 | Metastasis in a single lymph node more than 2 cm but not more than 5 cm in greatest dimension, or multiple lymph nodes, none more than 5 cm in greatest dimension |
N3 | Metastasis in a lymph node more than 5 cm in greatest dimension |
M—Distant metastasis | |
M0 | No distant metastasis |
M1 | Distant metastasis |
Histopathological grading | |
GX | Grade of differentiation cannot be assessed |
G1 | Well differentiated |
G2 | Moderately differentiated |
G3–4 | Poorly differentiated/undifferentiated |
Stage grouping | |||
Stage 0a | Ta | N0 | M0 |
Stage 0is | Tis | N0 | M0 |
Stage I | T1 | N0 | M0 |
Stage II | T2 | N0 | M0 |
Stage III | T3 | N0 | M0 |
Stage IV | T4 | N0 | M0 |
Any T | N1, N2, N3 | M0 | |
Any T | Any N | M1 | |
Table 6.2
WHO (2004 and 1973) histological grading of non-muscle-invasive bladder tumors
WHO (2004) grading |
Urothelial papilloma |
Papillary urothelial neoplasm of low malignant potential (PUNLMP) |
Low-grade papillary urothelial carcinoma |
High-grade papillary urothelial carcinoma |
WHO (1973) grading |
Urothelial papilloma |
Grade 1: well differentiated |
Grade 2: moderately differentiated |
Grade 3: poorly differentiated |
In contrast to the lower urinary tract, accurate staging of tumors of the upper tract is limited to tumor grade as depth cannot be assessed as biopsies do not usually provide deep or full-thickness specimens. Tumor grade, however, correlates well with the pathological grading and staging of nephroureterectomy specimens. Keeley et al. demonstrated a biopsy grade to surgical specimen grade relation of 90% [29]. Grade at biopsy corresponded with eventual stage, with 87% of low-grade biopsies staged pTa or pT1 and 67% of high-grade biopsies staged as T2 or T3 at surgery. The diagnostic accuracy of tumor grade allows selection of patients either for future endoscopic treatment or nephroureterectomy for those who are at risk of progression [23].
Other studies have demonstrated under-staging and grading of tumors at biopsy. Guarnizo et al. [30] found that for tumors graded Ta at biopsy, 45% were upstaged based on the surgical specimen. In a review of 30 nephroureterectomies in Bristol, 75% of preoperative biopsies corresponded accurately with grade at surgery. Of the remaining cases, 90% were under-graded at biopsy. Of 18 lesions graded G2 at biopsy, 6 were surgically staged as pT2 or above [26].
In contrast to 15% of bladder cancers, a significant 60% of UUT-TCC are invasive [31]. This is the reason nephroureterectomy has become the standard of treatment. It is an important consideration that any patient undergoing endoscopic treatment for UUT-TCC may potentially be denied a curative nephroureterectomy [28]. UUT-TCC is commonly multicentric, and unilateral upper tract multifocal tumors may account for up to 27% of all UUT-TCC [32]. Bilateral UUT-TCC occurs in 0.01–4% of cases.
Prognostic Factors
Staging is closely correlated with prognosis in UUT-TCC, with the stage and grade of tumor being the most important factors with regard to survival. Tumors that invade the muscle wall carry a very poor prognosis. The 5-year survival for a pTa tumor is >80% [10] compared to <50% of pT2/3 tumors and <10% for pT4 tumors [33, 34].
Lymphovascular invasion and extensive tumor necrosis (>10% tumor area) is associated with poorer outcomes [35–39]. The presence of CIS is associated with higher risk of recurrence and cancer-specific mortality [40].
Tumor location within the renal pelvis or ureter is no longer a prognostic factor according to recent data [41–43], even when adjusted for tumor stage [41, 44]. In addition, age and gender no longer accepted as adequate independent prognostic indicators [45–48]. Hydronephrosis on preoperative imaging is associated with more advanced disease and poorer outcomes [49].
Molecular markers such as E-cadherin, hypoxia-inducible factor (HIF), and telomerase RNA component have been heralded as prognostic markers [50] but have not yet been externally validated.
Management of Localized Disease
For patients with localized disease, the options for management include radical surgery (open/laparoscopic radical nephroureterectomy) or renal-sparing surgery (open/laparoscopic segmental resection or endoscopic treatment with or without adjuvant topical therapy).
Radical Surgery
Open Radical Nephroureterectomy
Le Dentu and Albarran performed the first nephroureterectomy with excision of the bladder cuff in 1891. Over the past 100 years, this has been the gold standard for treating UUT-TCC-allowing for complete tumor excision, good surgical margins, and assessment of disease spread and progression. UUT-TCC commonly presents multifocally within the urinary tract involved, therefore if there is a healthy contralateral tract it is the logical therapy. Recurrence rates in the contralateral tract are 6.5% at 15 years [51], whereas if only a simple nephrectomy is performed, the recurrence rate of UUT-TCC can be as high as 40% in the remaining ipsilateral stump [52]. Nephroureterectomy is therefore a safe curative therapy, and one should be aware of this when considering more conservative management options for patients.
Laparoscopic Radical Nephrectomy
This has become an accepted alternative to the open operation [32]. Laparoscopy offers reduced postoperative morbidity with no significant difference in disease-specific survival rates at 7 years in a study of laparoscopic versus open nephroureterectomy [53]. Specific concerns related to the laparoscopic approach are local seeding and port-site metastases.
Renal-Sparing Surgery
Segmental Resection
Segmental resection preserves the ipsilateral kidney whilst providing pathological information for staging and grading. Segmental distal ureteral resection is possible for low- and high-risk tumors [54, 55]. Complete distal ureterectomy is recommended for distal ureteral tumors that cannot be completely treated endoscopically. When the entire distal ureter is removed, a bladder psoas muscle hitch, a Boari flap, or both techniques may be required.
Open segmental ureterectomy and ureteroureterostomy is suitable for noninvasive grade 1 and grade 2 tumors of the proximal ureter or midureter too large for endoscopic treatment and for grade 3 or invasive tumors when nephron-sparing is required. In patients where renal-sparing is required but who have ureteral tumors that are numerous, multifocal but with low grade and stage, a subtotal ureterectomy which involves removal of long ureteral segments only may be appropriate [25]. Open resection of renal pelvic or calyceal tumors is now rare as it is technically challenging with higher recurrence rates compared to ureteral tumors [5]. Various techniques for laparoscopic distal ureterectomy and reimplantation have been reported [25] and early results are encouraging.
Endoscopic Treatment
Endoscopic management has gained acceptance in recent years. The aim is to ensure adequate cancer control while preserving renal function and the viability of the affected urinary tract. Approach to the tract can be made either antegradely in the same manner as a percutaneous nephrolithotomy or retrogradely via the ureter.
Percutaneous Approach
This approach allows tumor biopsy, resection, and/or cauterization. This is considered for low-grade noninvasive disease in the lower calyceal systems inaccessible or difficult to treat with ureteroscopy. There is a theoretical risk of tumor seeding in the tract and in perforations. Adjuvant therapy can be administered via a nephrostomy tube [5]. Recurrence rates following percutaneous therapy may be in the region of 30% for low-grade (1–2) tumors and 45% if low- and high-grade tumors are taken into account [56, 57]. This treatment modality is becoming less common due to advances in ureteroscopy [5].
Ureteroscopic Approach
Advances in ureteroscope technology have been vital in the progress of ureteroscopic management of UUT-TCC. With the development of smaller caliber rigid and flexible ureteroscopes, endoscopic management of ureteral and smaller renal collecting system tumors confers lower morbidity and also prevents tumor seeding in a closed system compared to the percutaneous approach [25]. Current flexible and semirigid ureteroscopes are small enough to allow accurate assessment of the ureter and collecting system. Flexible ureteroscopes are now produced with 180° upwards and downwards deflection allowing for accurate biopsy and ablation [58]. The Ho:YAG and Nd:YAG lasers in particular have allowed accurate treatment of larger tumors [23].
Ureteroscopic Management
Indications
Currently, there are three situations where ureteroscopic management is considered:
Existing or likely renal compromise. For patients with bilateral disease, solitary kidneys, or renal insufficiency, a renal-sparing approach is advocated. Ureteroscopic management can maintain the kidney and also urinary tract integrity, thus avoiding rendering the patient dialysis-dependent.
Where a major operation would carry a high risk. For those patients who are unfit for major surgery, either open or laparoscopic, or for whom the risks associated with such an operation are high, endoscopic management can be considered as it is less invasive.
Low-grade, low-stage disease that can be managed conservatively. These cases can be managed endoscopically, given accurate preoperative tumor assessment and strict postoperative follow-up. A sound evidence base is essential for this group of patients as they are foregoing potentially curative nephroureterectomy.
A further classification of patients according to indication is shown in Table 6.3 [23].
Table 6.3
Classification of indication for ureteroscopic treatment
Absolute | Patients who would not tolerate open surgery or would require dialysis |
Relative | Those with severe medical problems or multifocal disease |
Elective | Those with no contraindication to definitive surgery |
Palliative | Those with large or bleeding tumors who would not tolerate open surgery |
Ureteroscopic Technique
Ureteroscopy for upper tract TCC involves inspection of the tract using rigid and flexible scopes, urine sampling, biopsy of suspicious lesions, and laser ablation of visible tumors [32, 33].
The procedure commences with an initial rigid cystoscopy as upper tract tumors are associated with bladder cancers [25]. The ureteral orifices are inspected for visible hematuria. Cannulation of the relevant ureteral orifice is performed to allow aspiration of urine or saline washings for cytological analysis followed by a retrograde study of the upper urinary tract. Rigid ureteroscopy of the ureter is performed with placement of a guidewire to the level of the ureteroscope, not beyond the immediate field of vision. If any suspicious area or lesion is encountered, cytology should be taken before biopsies or intervention.
On reaching the limit of the rigid ureteroscope, the rigid ureteroscope is replaced by a small caliber flexible ureteroscope which is advanced into the renal pelvis. At this point, further urine can be aspirated for cytological analysis. Contrast is injected to aid systematic ureteroscopic inspection of the calyces. Tumor biopsies are taken followed by tumor ablation. For tumors that protrude from the ureteral orifice, ureteroscopic ablation or transurethral resection of the most distal ureter is performed.
A retrograde ureteral stent or ureteral catheter is inserted at the end of the procedure. The former is left in situ for a variable period to allow healing and the latter to facilitate administration of adjuvant therapy in the postoperative period.
Tumor Ablation
Tumor ablation can be achieved by three methods [25].
Particularly suitable for low-grade papillary tumors on a narrow stalk, the first involves debulking the tumor with grasping forceps or flat wire basket. The base of the tumor is then ablated with electrocautery or laser.
The second method involves the use of a ureteroscopic resectoscope (12 Fr) where an intraluminal tumor is resected to the base. Resection beyond the lamina propria is not attempted, particularly in the upper and midureter where the wall is thin and the risk of perforation high. For higher volume disease of the distal ureter, resection with a long standard resectoscope after initial dilatation has been described. This technique has largely been replaced, as ureteral resectoscopes are of such a large caliber that access is problematic.
The final method involves taking an initial biopsy followed by ablation of the tumor bulk, including the base, with either electrocautery or laser. Electrocautery via a 2–3 Fr Bugbee electrode fulgurates tumors but variable depth of penetration is an issue in the ureter. There is a high risk of stricture formation with circumferential fulguration [25]. Laser ablation can be performed with a holmium:yttrium–aluminum–garnet (Ho:YAG) or neodynium:yttrium–aluminum–garnet (Nd:YAG) laser source via flexible, small diameter fibers (200–1,000 μm).
The Ho:YAG laser is used in the ureter as it has minimal depth of penetration of less than 0.5 mm which minimizes full-thickness ureteral injury during use. It ablates the tumor efficiently and provides precise cutting with excellent hemostasis. Laser settings are 0.6–1.2 J at 8–10 Hz. The Nd:YAG laser offers deep tissue penetration of up to 5–6 mm and is more suited to larger, renal pelvic tumors. It causes coagulation necrosis of the tumor with subsequent sloughing. Hemostasis is excellent. Its use in the ureter is limited due to increased risk of perforation. Settings employed are 15 W for 2 s for tumor ablation and 5–10 W for 2 s for coagulation [25].
Adjuvant Topical Therapy
Ureteroscopic treatment is associated with high recurrence rates and tumor progression. Reducing the rate of recurrence or progression is important in the management of these patients [59]. Postoperative topical immunotherapy and chemotherapy have been employed with success in the treatment of bladder TCC. These agents have also been administered as adjuvant treatment for UUT-TCC to decrease tumor recurrence and progression [60–65]. The agents available for use include bacillus Calmette-Guerin (BCG), mitomycin C (MMC), and doxorubicin. BCG is commonly used as adjuvant therapy and also when a tumor has been incompletely treated.
Administration. Adjuvant therapy can be administered by infusion via a retrograde ureteral catheter, reflux from the bladder via a ureteral stent, or percutaneously via a nephrostomy. Keeley and Bagley [59] described their technique of mitomycin C instillation in the treatment of UUT-TCC following endoscopic ablation. In their series, a 6 Fr open-ended ureteral catheter was placed in the renal pelvis under fluoroscopic guidance. The integrity of the collecting system and position of the ureteral catheter were confirmed by injection of contrast via the catheter. The ureteral catheter was secured to a urethral catheter under gravity drainage. Instillation was commenced after resolution of any visible hematuria to reduce the risk of systemic absorption. Three doses of 10 ml of mitomycin C (40 mg in 30 ml normal saline) were given at 2-hourly intervals. Each instillation was given over 2 min and the ureteral catheter clamped for 10 min following instillation. After the third instillation, both catheters were removed.
Safety. Concerns regarding the use topical therapies in the upper urinary tract include patient discomfort during instillation, local effects, systemic absorption and toxicity, and sepsis. Low pressure administration is required to prevent systemic absorption and sepsis. In the series by Keeley and Bagley [59], all 19 patients treated with MMC did not complain of discomfort during instillation with no cases of systemic toxicity. One patient had evidence of a local reaction with necrotic debris and overlying calcifications following extensive laser ablation of a renal pelvic tumor followed by MMC. This appearance persisted for at least 12 months. Eastham and Huffman [60] reported no systemic side effects or pyrexia in the seven patients treated with MMC.
However, out of 14 patients treated with MMC in the series by Martinez-Piero et al. [62], 1 patient died from aplastic anemia and sepsis secondary to extravasation. Their method of MMC delivery was not described.
With BCG therapy, the most common complication is sepsis but systemic BCG infection or granulomatous infection of the kidney can occur. Unfortunately, the upper urinary tract does not tolerate granulomas as easily as the bladder, as they can lead to obstruction and loss of function in our experience.
Ureteroscopic Complications
Ureteroscopic surveillance and treatment of upper tract tumors have a low rate of complications. The stricture rate following ureteroscopy is around 10% and the blood transfusion rate is very low.
Advantages of Ureteroscopic Management
Ureteroscopic treatment confers several advantages. A major advantage is the preservation of renal function which is important in patients where renal compromise would present a poor outcome. It is desirable in patients with low-stage and low-grade disease for whom endoscopic management would avoid radical surgery. For those with major co-morbidities, ureteroscopy is less invasive than radical surgery and confers a decreased risk of morbidity and mortalilty. A further benefit is that the integrity urinary tract is maintained thus limiting tumor spread.
There are few studies comparing outcomes for nephroureterectomy and ureteroscopic management of UUT-TCC [32]. Endoscopic management has a similar prognosis to nephroureterectomy if patients are well-selected, which is in turn dependent on accurate preoperative assessment [32]. In one study, Keeley et al. looked at 38 patients (41 kidneys) with UUT-TCC treated ureteroscopically. Complications during surgery were related to existing cardiopulmonary disease. Two patients subsequently developed urethral strictures but no patients required blood transfusions or emergency surgery for bleeding [23].
Disadvantages of Ureteroscopic Management
Ureteroscopic equipment is obviously small, and there are limits both to the extent to which biopsies can be performed and the amount of tumor that can be resected. Failure of ureteroscopic treatment is related to tumor size [23], hence the importance of accurate diagnostic assessment prior to ureteroscopy.
It has been noted that patients with grade 2 tumors are at particular risk of being understaged at biopsy [10]. However, the concurrent use of ureteroscopic biopsy is more accurate than using cytology, imaging, and retrograde studies alone. Thus clinicians should be cautious in interpreting biopsy results, especially for the elective group of patients with biopsy suggestive of middle-grade disease.
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