# Endoscopic Management of Upper Tract Urothelial Carcinoma

Authors: K. Moore; J. Khastgir; M. Ghei
Journal: Advances in Urology
 (2009)

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## Abstract

Nephroureterectomy is currently the gold standard for management of upper urinary tract urothelial carcinoma despite it results. This review article in the loss of a renal unit.  The ultimate aim of endoscopic management of this condition is cancer control whilst preserving renal function and the integrity of the urinary tract. Endoscopic treatments of upper tract TCC include the antegrade percutaneous and retrograde ureteroscopic approaches.  This review article summarizes the endoscopic management of upper tract urothelial carcinoma, surveillance of the disease after endoscopic management and adjuvant therapy. The main message regarding endoscopic management of upper tract urothelial cancer is that patients must be carefully selected. Patient selection is based on tumour size, grade, and multifocality. Single low-grade tumours, less than 1.5 cm in size, generally have a good outcome with endoscopic treatment provided that they have regular ureteroscopic surveillance. Ureteroscopic treatment of high-grade tumours is essentially palliative. It is essential that patients are motivated and compliant as lifetime follow-up is necessary. However, until large randomized trials with long-term follow-up are performed, endoscopic management cannot be considered a standard treatment and should be limited to poor performance status patients.


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## Body

## 1. Introduction

Primary urothelial carcinoma of the upper urinary tract accounts for 5%
of all urothelial tumours and 7–10% of all kidney tumours.Nephroureterectomy including a cuff of
bladder has been the “gold standard” treatment despite the associated morbidity
and loss of a renal unit.Currently,
laparoscopic approaches have reduced the size of the incision, length of
hospital stay, postoperative pain, and morbidity and give oncological outcomes
similar to those of open surgery.However, a laparoscopic nephroureterectomy is still radical surgery that
does not spare the renal parenchyma.The ultimate aim of endoscopic management is cancer control whilst
preserving renal function and the integrity of the urinary tract.These procedures were initially reserved for
patients with solitary kidneys, bilateral disease, or renal insufficiency but
are starting to gain acceptance in the management of small, low-stage,
low-grade tumours in patients with normal contralateral kidneys. Endoscopic treatment of the upper urinary
tract includes antegrade percutaneous and retrograde ureteroscopic approaches
which were first described in the mid 1980s.


## 2. Tumour Grade and Stage

A key point in
choosing the optimum treatment for upper tract urothelial carcinoma is correct
staging by endoscopic evaluation and biopsy.There are significant differences in 5 year survival rates ranging from
60–90% in Ta/1 and CIS disease to only 5% in T3/4 disease. The most important factors for survival are
tumour stage, grade, and multifocality [1].In a study
of 130 consecutive nephroureterectomy specimens, tumour stage significantly
correlated with tumour grade. Five percent of patients with low-grade UTUC had
pathologic stage pT2 or higher, while 65% of patients with high-grade tumours
had pathologic stage pT2 or higher [2]. Similarly, Murphy et al. reported that
47 of 49 patients (96%) with grade 1 upper tract transitional cell carcinoma
also had stage 1 disease [3].Tumour grade is also related to
recurrence rate with Zincke reporting that only 5% of 21 patients with grade 1
or 2 developed a recurrence compared with 50% with grade 3 or 4 disease [4].Orihela reported that in 14 patients
recurrences were almost exclusively in those with multifocal, high-grade,
invasive tumours [5].In general,
recurrences are unlikely in patients with single, low grade small tumours
confined to the mucosa with no history of concurrent urothelial tumours
elsewhere in the urinary tract.Upper
tract recurrence rates were 28.5% in a group with a history of bladder lesions
compared to 16.6% in a group without bladder disease [6].However,
diagnosis of ureteric lesions is not straight forward. In a study by El-Hakim et al., ureteroscopic
appearances of upper tract urothelial carcinoma was only 70% accurate in
determining the grade and they suggested biopsies must be taken to in order to
determine the true grade [7]. In
contrast, a study by Keeley et al. showed transitional cell carcinoma grade on
ureteroscopy accurately predicted tumour grade and stage in the surgical
specimens. They observed that, of the 30 low or moderate grade ureteroscopic specimens, 27 (90%) proved to be
low or moderate grade transitional cell carcinoma in the surgical specimens,
while 11 of 12 high grade ureteroscopic specimens (91.6%) proved to be high
grade transitional cell carcinoma (P<.0001).In 30 low or moderate grade ureteroscopic specimens, 26 (86.6%) had a low
stage (Ta or T1) tumour. In contrast, 8
of 12 high grade ureteroscopic specimens (66.7%) had invasive tumour (stage T2
or T3) in the surgical specimen (P=.0006) [8]. These same authors also noted
how crucial the techniques for handling and processing the small samples obtained
via ureteroscopy are.They found that sending multiple samples,
including saline washes before and after biopsy, improved the ability to grade
tumours ureteroscopically from 42.9% to 90% [8] .A further study
by Williams et al. to determine the accuracy of ureteroscopic biopsy in
predicting the histopathology of upper tract TCC looked at 30 biopsies taken
between 1998 and 2006.At
nephroureterectomy, 2 cases were found to have no tumour. Of the remaining 28 cases, the biopsy grade
proved to be identical in 21 (75%). 17
of 25 (68%) of grade 1-2 ureteroscopic specimens had a low stage (T0, Ta, or
T1) tumour.In contrast, 3 of 5 (60%)
high grade specimens had invasive tumour (T2 or T3).They concluded that ureteroscopic inspection
and biopsy provided accurate information regarding the grade and stage of upper
tract TCC [9].Tumour size also
appears to influence recurrence rate.
One study reported that only 7 of 19 renal units (36%) with tumours
larger than 1.5 cm were ever rendered tumour free and 3 of 6 tumour free renal
units subsequently developed a recurrence.In contrast, 20 of 22 (91%) of renal units with initial tumours less
than 1.5 cm were rendered tumour free and only 5 (25%) tumour free
kidneys had recurrences [10].This
finding was echoed by Johnson et al. who found that patients presenting with
tumours >1.5 cm in size had a higher incidence of recurrence and recurred
earlier [11]. Johnsonet al. confirmed the aggressive nature of high
grade disease.In a cohort of 63
patients, tumour progression was seen in 83% of patients with high grade
ureteric urothelial carcinoma when nephroureterectomy was not performed [11].


## 3. Ureteroscopic Management

Developments in ureteroscopic instruments and techniques now allow for
ureteroscopic access to the entire upper urinary tract.Small diameter rigid and flexible ureteroscopies
with greater deflecting abilities have been combined with endoscopic biopsy
techniques and devices for tissue ablation to offer practical approaches to
upper urinary tract tumours.
Particularly, the holmium:YAG and neodymium:YAG lasers used to cauterize
and ablate tumours, delivered through small-diameter, flexible fibres, have
allowed treatment of relatively large tumours whilst maintaining homeostasis [11].Electrosurgical techniques were first used
for the treatment of ureteric neoplasms. They are used in a similar way to resectoscopes for other procedures but
because of the rigid design of the resectoscope, its use is primarily confined
to the distal ureter.Given the thin
wall of the ureter, care should be taken to avoid resecting through the full
thickness of the wall and also to avoid fulgurating a large area of the ureter
as this increases the chances of subsequent stricture formation.Simple fulguration with an electrocautery
probe is another electrosurgical technique suitable for very small lesions or
for the base of the tumour after removal of the bulk of the lesion [12].The neodymium:YAG laser has been used widely for the
treatment of both bladder and upper tract tumours.The fibre is directed at and placed in close
approximation to the tumour, activated at 20 to 30 w and moved over the surface
to coagulate the tissue.The laser
penetrates to a depth of 5-6 mm. The
coagulated tissue is removed with graspers to expose further portions of the
tumour which can be treated in the same fashion.The holmium:YAG laser both coagulates and ablates
tissue penetrating to a depth of 0.5 mm.This is useful for ureteric lesions as it can ablate and remove an
occlusive tumour opening up the lumen.Irrigation is needed to clear the visual field of tissue debris during
treatment.The two lasers can be used in combination.The neodymium:YAG laser, penetrating to a
depth of several millimetres, is used to coagulate the major volume of the
tumour, then the coagulated tissue can be removed with the holmium:YAG laser [12].Schmeller
compared laser ablation with electrocautery and found fewer strictures
developed in the laser group [13].However, Martinez-Pineiro et al. found that their laser results did not offer
significant benefit compared with electrocautery [6]. Data on electrocautery
versus laser treatment is scant (probably due to the small cohort of patients
being treated in this manner) but to date there is no convincing evidence that
the efficacy of tumour destruction is affected by the method used.All ureteroscopic interventions
should be followed with short term ureteral stenting to prevent any
postoperative obstructive sequelae [12].Complications of ureteroscopic management occur in 8–13% and are mostly
minor including perforation in 1-4% (managed by ureteric stenting or
percutaneous drainage) and ureteric strictures in 4.9–13.6%.Most strictures can be managed by stenting, laser incision, or balloon
dilatation [14].In a study by Keeley et al., between 1985 and 1995, 92 patients were
diagnosed with upper tract TCC. 46 had a
diagnostic ureteroscopy followed by open extirpation and 46 had some form of
endoscopic treatment.8/46 had open
surgery following endoscopic therapy and 38 (41 kidneys) had ureteroscopic
treatment and follow-up.Semirigid and
flexible ureteroscopes were used to examine the collecting system, tumours were
biopsied then treated with fulguration, the neodymium:YAG laser and/or the
holmium:YAG laser. Patients were treated
every 6 to 12 weeks until tumour free and then followed up with further
ureteroscopy.At least 1 follow-up
ureteroscopic examination was performed in all 38 patients.Of the 41 renal units, 28 (68%) were rendered
tumour free after an average of 1.57 ureteroscopic treatments.Complications were generally related to
comorbid disease, 1 patient with a solitary kidney developed an episode of
acute renal failure with clot retention but recovered to baseline renal
function.No patient required a blood
transfusion or emergency open surgery for bleeding.2 patients had ureteric strictures, 1 with a
history of pelvic radiotherapy for bladder cancer and 1 following neodymium:YAG
laser treatment of a proximal ureteric tumour.No ureteric perforations were noted [10].Chen and Bagley
followed 23 patients with a normal contralateral kidney for a mean of 35 months
after initial ureteroscopic treatment of upper tract transitional cell
carcinoma (range 8 to 103). 22 tumours were grade 1 to 2 and 1 was grade 2 to
3.There were multiple recurrences
(treated ureteroscopically) in 15 of 23 patients (65%) and no recurrences in 8
(35%). Average time to recurrence was 9.5 months (range 2 to 53) with an
average of 4 recurrences (1 to 14). There were no metastases or mortality from
transitional cell carcinoma. At
completion of the study, 4 patients (17%) had persistent disease and 4 (17%) elected to undergo nephroureterectomy.
Complications included ureteral strictures in 2 patients treated for distal
ureteral tumours. The strictures were treated with endoscopic dilation [15].A study from Madrid
reported a
failure of ureteroscopy in 11 of 39 patients (28.2%), mainly due to inability
to reach pelvic tumours or to destroy the tumour. Four of these patients were successfully
treated by a percutaneous approach and 7 required nephroureterectomy [6]. Similarly, Blute et al. reported a high
ureteroscopic failure rate in 14/22 (63.6%) of patients with renal pelvic
tumours, indicating that ureteroscopy is not the best procedure for most
tumours of the renal pelvis and that these neoplasms are best managed
percutaneously [16].


## 4. Percutaneous Nephroscopic Management

Although ureteroscopy has the theoretical benefit of preserving a closed
urinary system, percutaneous access may be necessary when tumours are not
accessible via a retrograde route or for larger tumours.Percutaneous nephroscopy offers better
visualisation of the renal pelvis while accommodating larger calibre
instruments capable of handling a larger tumour burden [12].After establishing a percutaneous tract, the lesion is initially
biopsied and then bebulked.As there is
a larger access tract, cold cup biopsy forceps can be used through a standard
nephroscope or a cutting loop from a resectoscope.The base of the lesion is resected and sent
for histological evaluation and haemostasis is achieved by electrocauterey or
laser ablation as previously described.The established nephrostomy tract can be maintained, allowing for
repeated treatment or administration of topical adjuvant therapy [12].Complication rates with the percutaneous approach are low and include
blood transfusion in<20% and less commonly, PUJ obstruction from stricture,
adjacent organ injury, and pleural injury [1].Tumour seeding along the nephrostomy tract has been reported [17]. Larger series though, failed to find tract
recurrences confirming that this phenomenon is rare. Precautions suggested to minimize seeding
include use of an Amplatz sheath to decrease intrarenal pressure during
manipulations and immediate irrigation of the collecting system and percutaneous
tract with a 5-florouracil solution.
One author suggested placing a radioactive iridium wire in the
percutaneous tract [18].Goel et al.
reported on 5 year outcomes of 24 patients who underwent primary percutaneous
resection of the urothelial tumour.
Patients with low stage pT0-1 disease were treated primarily with
percutaneous surgery.Patients with
multi-segmental pelvicaliceal system involvement, stage greater than pT1, high
grade histology or additional ureteral tumours were considered for
nephroureterectomy.Topical chemotherapy
(mitomycin C or epirubicin) was administered via nephrostomy tube or
intravesical instillation after Double-J stent insertion. Surveillance included
upper tract cytology, nephroscopy or fiberoptic ureterorenoscopy.Of the 24, 2 cases had squamous cell carcinoma, 5 had grade 3
transitional cell carcinoma, 15 had grade 1 to 2 transitional cell carcinoma
and 2 had no tumour. Control was
established with initial percutaneous resection in 18 (75%) cases and second look
nephroscopy in 4.All patients with high-grade
disease died of malignancy except one (with no further treatment) and 6 of the
15 patients with low-grade noninvasive transitional cell carcinoma underwent
nephroureterectomy during follow-up either due to progression of disease,
concomitant tumour, or complications.Two patients with solitary kidneys died of renal failure unrelated to
malignancy.High grade tumours or
tumours greater than T1 were treated with nephroureterectomy early during
management. There was no perioperative
mortality and in 9 (60%) of the low-grade cases the kidneys were preserved at
mean follow-up [19].In a more recent study, Palou et al. retrospectively reviewed 34
patients who had percutaneous management of their upper tract TCC.15% had grade 3 tumours with either a
solitary kidney or bilateral disease.During a 4.25-year follow-up, recurrence was found in 44% at a median
time of 24 months.9 cases required nephroureterectomy.Renal
preservation was achieved in 74%. Overall
survival and cancer specific survival was 71% and 93%, respectively [20].Rouprêt et al. reported on the results of 24 patients who underwent a
percutaneous approach to their tumour.Median follow-up was 62 months with recurrences detected in 8/24 at a
median time of 17 months. 3 recurrences
were in the ipsilateral ureter, 1 in the contralateral ureter, and 4 in the
bladder. Five patients with high grade
and/or invasive tumour subsequently underwent an open nephroureterectomy, one
immediately and the others during follow-up.5/24 (20.8%) of the patients have died, and 4 of these deaths were
attributed to disease progression. They
reported 5-year disease specific survival rates as 79.5% and tumour free
survival rates as 68%. 4 patients
developed perioperative complications; 3 required blood transfusion and 1
developed a collection (which was managed with antibiotics) after inadvertent
puncture of the bowel [21].


## 5. Surveillance

Unlike traditional management with nephroureterectomy, endoscopic treatment
of upper tract TCC requires strict ureteroscopic surveillance as both the
ureteroscopic and percutaneous approach are associated with a high risk of
ipsilateral recurrence. Endoscopic
follow-up has been shown to be more sensitive than radiological examination as
IVU may miss up to 75% of small recurrences [9]. Surveillance ureteroscopy is usually
performed at 3 and 6 months, then 6 monthly for a year, then annually, and it
requires a counselled, well-motivated patients to strictly adhere to the follow-up
protocol.Surveillance needs to be
performed for an indefinite
time interval as recurrences have been reported after 8 years of follow-up [22].In an effort to reduce the anaesthetic risks, costs and time of
surveillance, a study from New York
reported on their 16 year experience of office-based ureteroscopy for
surveillance of TCC after initial endoscopic ablation.10 patients were treated with endoscopic
ablation for TCC. A total of 67 (range 1
to 19 per patient) surveillance ureteroscopies were performed in the office
setting. This procedure was performed
without anaesthetic (only lignocaine jelly to the urethra) using a flexible ureteroscope.This revealed 7 upper tract TCC recurrences
in 5 patients.A thorough ureteroscopic
examination in the operating room revealed that only one patient had more
extensive disease than was indicated in the office based ureteroscopy.All patients tolerated the office based
procedure well with minimal discomfort.There were no acute complications [23].Urinalysis with
dipstick and microscopic examination is an attractive surveillance tool as it
is noninvasive, inexpensive, and can be performed in an outpatient setting
giving an immediate result. In patients
with recurrent upper tract transitional cell carcinoma, urinalysis had a low
sensitivity (36.3%) but high specificity (90.6%) in detecting recurrent
disease. This low detection rate may be due to the low grade nature of most
upper tract transitional cell carcinomas managed with local resection as low grade
tumours are less likely to shed diagnostic cells [24]. In a series by Xia, voided cytologies
were positive in 33% of grade 1, 71% of grade 2 and 100% of grade 3 upper tract
tumours. In recent years adjunct
diagnostic techniques such as immunocytologic staining or fluorescence in situ
hybridisation have been used for evaluating the presence or absence of
malignant cells in urine [25].


## 6. Adjuvant Therapy

A substantial proportion of patients with endoscopically managed upper
tract urothelial carcinoma will develop a recurrence.Adjuvant topical immunotherapy or
chemotherapies have been used in an attempt to reduce the risk of tumour
recurrence.The most commonly instilled
agents are mitomycin-C and BCG.Method
of instillation, depending on the approach to the tumour, can be performed via
a retrograde ureteral catheter or through a percutaneous nephrostomy tube.Most published reports involve few patients
with short follow-up and a relatively high complication rate.Orihuela and Smith found a lower recurrence rate (16.6% versus 80%) in those
patients treated with BCG compared to those who did not recieve adjuvant
treatment but a further study by the same group showed no survival advantage [5]. Sharpe et al. reported on the use of BCG via
retrograde ureteral catheters in 17 kidneys of 11 patients with abnormal
cytology. At a mean follow-up of 36
months cytology had normalised in 8 of 11 patients.1 patient developed a fever and was treated
with antituberculous drugs.In a further
study of 18 patients treated with BCG, 7 developed fever on 14 occasions and 1
patient died of sepsis despite prophylactic IV antibiotics.In terms of efficacy, no significant
difference was found between the patients treated with BCG and those who were
not [26].Keele et al. looked at 19 patients who underwent a total of 28
treatments with mitomycin C after ureteroscopic treatment for high volume,
recurrent or multifocal disease.
Following 1 to 4 treatments with MMC, 11 of 19 (58%) were rendered free
of disease, 4 required nephroureterectomy for persistent or recurrent disease
and no patients developed local or distant progression of disease or any
significant side effects[26].In a study that reported on 14 patients who
received MMC, one patient died of aplastic anaemia and sepsis secondary to
extravasation during treatment.This
same study also found a lower rate of recurrence among patients treated with
MMC or BCG compared to those treated with thiotepa or oral 5-fluorouracil [6].As yet, no study has shown statistical improvement regarding survival
and recurrence rates and no protocol of treatment has been accepted.Randomized multicenter trials are needed to
assess the efficacy of adjuvant agents.


## 7. Endoscopic Treatment versus Radical Nephroureterectomy

Rouprêt
et al. compared the outcomes in patients who had undergone either open
nephroureterectomy or endoscopic surgery (ureteroscopic or percutaneous
management) for upper urinary tract transitional cell carcinoma.A retrospective review of the data for
patients treated surgically for upper urinary tract transitional cell carcinoma
from 1990 to 2004 was performed. Data
were analyzed for 97 patients. The
surgical procedure was open nephroureterectomy in 54 patients, ureteroscopy in
27, and percutaneous endoscopic ablation in 16.
In patients with low-grade tumours (n=46), the 5-year
disease-specific survival rate after nephroureterectomy, ureteroscopy, and
percutaneous endoscopy was 84%, 80.7%, and 80%, respectively (P=.89);
the corresponding 5-year tumour-free survival rates were 75.3%, 71.5%, and 72%
(P=.78) [27].Lee et al. had similar findings when reviewing their 13 year experience
of percuaneous management of upper tract urothelial carcinoma.They found no significant difference in
overall survival when compared with nephroureterctomy.Regardless of treatment modality, patients
with low grade lesions did well where as those with high grade lesions were
predisposed to tumour recurrence and progression.Also, recurrence rates of bladder TCC appear
to be similar after radical nephrectomy or endoscopic surgery [28].Boorjian et al. reviewed 121 patients who underwent a nephroureterectomy
for upper tract TCC over a 10-year period.
In comparing patients who underwent nephroureterectomy on the basis of
positive cytology findings and filling defects on contrast imaging (n=34) with
patients who had nephroureterectomy after ureteroscopic biopsy (n=75) and
patients who had nephroureterectomy after ureteroscopic biopsy and laser
ablation (n=12), they found no significant difference in postoperative disease
status.Disease free rates in the 3
groups were 85.3%, 81.3%, and 83.3%, respectively [29].


## 8. Conclusions

Many reports of endoscopic surgery for upper tract urothelial carcinoma
have emerged but only a few have a reasonable number of patients. Most series are small, with all types of
indications (elective and palliative) and tumour characteristics (grade, stage,
size, location).The main
message from series of endoscopic management of upper tract urothelial cancer is
that patients must be carefully selected.
Patient selection is based on tumour size, grade, and
multifocality.Single low-grade tumours,
less than 1.5 cm in size generally have a good outcome with endoscopic treatment
provided they have regular ureteroscopic surveillance.Ureteroscopic treatment of high-grade tumours
is essentially palliative.It is
essential that patients are motivated and compliant as lifetime follow-up is necessary.Recurrence rates are high but these recurrences can be treated with
further endourological therapy or radical surgery as studies have shown that
endological manipulation does not have a negative impact on survival.The endoscopic approach can be mooted as an alternative approach to
nephroureterectomy in poor performance status patients, but, until large,
randomized trials with long-term follow-up are performed, it cannot be considered
as a standard treatment.



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