Francis X. Keeley

Diagnostic Accuracy of Ureteroscopic Biopsy in Upper Tract Transitional Cell Carcinoma

PURPOSE Our aim was to determine the accuracy of ureteroscopic biopsies and cytological techniques compared to open surgical specimens of upper tract transitional cell carcinoma. MATERIALS AND METHODS From 1985 to 1995, 51 cases of upper tract transitional cell carcinoma were diagnosed ureteroscopically and distal ureterectomy or nephroureterectomy was performed. Each patient underwent direct ureteroscopic inspection and biopsy. Fresh samples were delivered to the cytopathology laboratory, where they were examined using cytospin and smear. A cell block was prepared when visible tissue was present. Grades of ureteroscopic biopsies were compared to grades and stages of surgical specimens in 42 cases. RESULTS Cytological evaluation was positive for malignancy in 48 of the 51 cases (94.1%). Grading of ureteroscopic specimens was possible in 42 cases (82.4%). Transitional cell carcinoma grade on ureteroscopy accurately predicted tumor grade and stage in the surgical specimens. Of 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 the 12 high grade ureteroscopic specimens (91.6%) proved to be high grade transitional cell carcinoma (p < 0.0001). Of 30 low or moderate grade ureteroscopic specimens 26 (86.6%) had a low stage (Ta or T1) tumor. In contrast, 8 of 12 high grade ureteroscopic specimens (66.7%) had invasive tumor (stage T2 or T3) in the surgical specimen (p = 0.0006). CONCLUSIONS Ureteroscopic inspection and biopsy combined with cytological techniques provide accurate information regarding grade and stage of upper tract transitional cell carcinoma.

Ureteroscopic Treatment and Surveillance of Upper Urinary Tract Transitional Cell Carcinoma

PURPOSE We determined the efficacy of ureteroscopic treatment of upper urinary tract transitional cell carcinoma. MATERIALS AND METHODS Of 92 patients diagnosed with upper urinary tract transitional cell carcinoma at our institution from 1985 to 1995, 38 (41 kidneys) underwent ureteroscopic treatment and followup. Semirigid and flexible ureteroscopes were used to examine the collecting system. Tumors were biopsied, and treated with fulguration, the neodymium:YAG laser and/or the holmium:YAG laser. Patients were treated every 6 to 12 weeks until tumor-free and then followed on a strict endoscopic protocol. RESULTS Mean and median followup was 35.1 and 26 months, respectively (range 3 to 116). Grading of ureteroscopic biopsies was possible in 40 of 41 cases. Initial grading of tumors was low (grade 1 or 1 to 2) in 21 kidneys, grade 2 in 14 and grade 3 in 5. Of 41 kidneys 28 (68%) were documented as tumor-free ureteroscopically at some time following treatment, including 8 (29%) with subsequent recurrences that were treated endoscopically and 24 (86%) with no evidence of disease at the most recent followup. No patient to date has had progression of disease during endoscopic followup. High tumor grade, size and multifocality were significantly associated with tumor persistence and recurrence. Location in the kidney versus ureter was not a significant prognostic factor. Of the recurrent tumors 75% were not identified radiographically but were only discovered endoscopically. Two of 8 kidneys removed after endoscopic treatment had no tumor stage (pT0). CONCLUSIONS Endoscopic treatment of upper urinary tract transitional cell carcinoma is a reasonable method to treat carefully select patients based on strict indications. Complete endoscopic followup at regular intervals is essential to rule out recurrences.

ADJUVANT MITOMYCIN C FOLLOWING ENDOSCOPIC TREATMENT OF UPPER TRACT TRANSITIONAL CELL CARCINOMA

PURPOSE A variety of topical agents have been used for transitional cell carcinoma of the upper tract. Mitomycin C has limited systemic absorption when given intravesically because of its high molecular weight. We reviewed our experience with mitomycin C following endoscopic treatment of upper tract transitional cell carcinoma. MATERIALS AND METHODS Since 1991, 19 patients (21 renal units) have undergone a total of 28 treatments with mitomycin C for high volume, recurrent or multifocal transitional cell carcinoma. Of the 19 patients 12 had an absolute indication for nephron sparing treatment. Following ureteroscopic biopsy and treatment of upper tract transitional cell carcinoma, 40 mg. mitomycin C in 3 divided doses was instilled via a ureteral catheter, which was clamped between doses to give an exposure time of 30 minutes. Eighteen patients have undergone ureteroscopic surveillance following a total of 26 treatments. RESULTS No systemic side effects occurred during or after treatment with mitomycin C. One patient had a prominent local inflammatory reaction following neodymium:YAG ablation and mitomycin C treatment of a renal pelvic tumor. The average size of the treated tumors was 17 mm. (range 5 to 30). The grade of the tumors (when known) was 1 in 5 patients, 1 to 2 in 2, 2 in 8 and 3 in 4. Most tumors were treated with either neodymium:YAG (6 cases) or holmium:YAG laser (8) or a combination of both (8). Following 1 to 4 treatments with mitomycin C 11 of 19 evaluable renal units (58%) were rendered free of disease. Six of those 11 renal units (54%) had an ipsilateral recurrence after a mean of 30 months of followup, 4 of which were treated endoscopically, and 7 (64%) are now disease-free without extirpative surgery. Four patients have undergone nephroureterectomy for persistent or recurrent disease. No patient has suffered local or distant progression of disease. CONCLUSIONS Instillation of mitomycin C for upper tract transitional cell carcinoma appears to be safe and can be considered for adjuvant treatment in select cases. More data are necessary to determine its efficacy.

Correlation of upper-tract cytology, retrograde pyelography, ureteroscopic appearance, and ureteroscopic biopsy with histologic examination of upper-tract transitional cell carcinoma.

PURPOSE To determine the accuracy of radiographic studies, ureteroscopy, biopsy, and cytology in predicting the histopathology of upper-tract transitional cell carcinoma (TCC). MATERIALS AND METHODS From 1998 to 2006, 46 upper-tract lesions were diagnosed ureteroscopically and underwent nephroureterectomy, and 30 of them were subjected to direct ureteroscopic inspection and biopsy. Fresh samples were delivered to the cytopathology laboratory and histology samples were prepared whenever visible tissue was present. Radiological, ureteroscopic, cytology, and biopsy data were compared to the actual grades and stages of these 30 surgical specimens. RESULTS Retrograde ureteropyelography was suggestive of malignancy in 29 of 30 cases, but did not predict the grade or stage accurately. Cytology was positive for malignancy in 21 of 30 cases (70%). Grading of ureteroscopic specimens was possible in all cases. At nephroureterectomy two cases were found to have no tumor (T(0)). Of the remaining 28 cases, the biopsy grade proved to be identical in 21 (75%). Grade 1 or 2 ureteroscopic specimens had a low-stage (T(0), T(a), or T(1)) tumor in 17 of 25 (68%); in contrast, 3 of 5 (60%) high-grade specimens had invasive tumor (T(2) or T(3)). For patients with grade 2 ureteroscopic specimens, combining exfoliated cell cytology and biopsy grade improved the accuracy in predicting high-stage and high-grade disease. CONCLUSIONS This study confirms previous findings that ureteroscopic inspection and biopsy provides accurate information regarding the grade and stage of upper-tract TCC. Combining exfoliated cell cytology improves the predictive power of biopsy grade 2 disease for high-risk specimen grade and stage. Our data suggest that ureteroscopic findings may predict muscle invasion.

Relief of Stent Related Symptoms: Review of Engineering and Pharmacological Solutions

PURPOSE We review the recent publications on developing engineering and pharmaceutical agents to alleviate stent related symptoms, and examine basic science studies that may support a particular approach. MATERIALS AND METHODS Data on randomized controlled trials for relief of stent related symptoms were analyzed. Studies involving engineering and pharmacological agents to resolve stent related morbidity were assessed separately. RESULTS A variety of physical characteristics of stents, including materials, diameter, length and shape, have been modified to reduce stent related symptoms. Numerous studies have been conducted to engineer the ideal stent without clear and definite conclusions. There are mixed results with materials and negative results with shape. Appropriate stent length appears to be important but decreased diameter has not been shown to help. A recent study using a ketorolac eluting stent showed no significant benefit. Even with the best material and length it appears that patients still have significant stent related symptoms. To relieve stent related symptoms several classes of oral medications have been proposed for off-label use based on intuition or experience. Recently prospective, randomized, placebo controlled trials have been performed, along with basic science studies regarding the pharmacology of the ureter. They showed a clear and consistent beneficial effect of alpha1-blockers in patients with indwelling ureteral stents. CONCLUSIONS Although there have been many advances in stent composition, construction geometry and design, the ideal stent has yet to be engineered. By contrast, the oral administration of alpha-blockers has shown the greatest reduction in stent morbidity.

New Ureteral Stent Design Does Not Improve Patient Quality of Life: A Randomized, Controlled Trial

PURPOSE Ureteral stents result in significant morbidity in many patients. Manufacturers have altered stent design and composition to minimize symptoms. The Polaris™ stent is made of a Percuflex® combination, providing a firm proximal aspect with a softer distal aspect to minimize symptoms. In this prospective, randomized study we compared symptoms and quality of life after stent insertion to determine whether this stent is better tolerated than the InLay® stent. MATERIALS AND METHODS Between September 2002 and September 2006 we randomized 159 patients requiring stent insertion for stone disease to receive the InLay or the Polaris ureteral stent. Patients were asked to complete the validated Ureteral Stent Symptom Questionnaire 2 weeks after stent insertion and 1 week after removal. RESULTS A total of 98 patients completed and returned each questionnaire, including 45 with the InLay and 53 with the Polaris. There were no significant differences between the groups on any health domain assessed. In the InLay and Polaris groups 91% and 94% of patients experienced pain with the stent in situ, which decreased to 40% and 43%, respectively, after stent removal. The urinary symptom score with the stent in situ was equal in the 2 groups (32, maximum 55). Of the InLay and Polaris groups 60% and 66% of patients, respectively, would be against receiving a further stent due to symptoms (p = 0.79). CONCLUSIONS The Polaris stent, designed with the specific aim of improving urinary symptoms and pain associated with ureteral stents, continues to have a significant detrimental effect on patient quality of life.

Ureteroscopic Management of Upper-Tract Urothelial Cancer : An Exciting Nephron-Sparing Option or an Unacceptable Risk?

PURPOSE To discuss the merits of the endoscopic management of upper-tract transitional-cell carcinoma (UTTCC). We present original data from our institution over an 8-year period and a review of some of the world literature. A discussion of the overall suitability of this modality for both clinician and patient is presented. PATIENTS AND METHODS A retrospective chart review was performed comprising operative logs, departmental databases, and pathologic registers. These sources were analyzed, and data were collected on all patients who underwent ureteroscopic treatment of UTTCC. Patients with at least 6 months of follow-up were included in the study. RESULTS Forty-five patients (mean age 65 yrs) were identified who had undergone ureteroscopic treatment for UTTCC with either therapeutic or palliative intent between 1998 and 2006. Of these, 19 procedures were performed electively in patients with normal contralateral kidneys. Those patients with low-volume, low-grade tumors on biopsy and negative results of urinary cytologic evaluation recovered well, with few recurrences. None of this group progressed to radical surgery. Of 12 patients never considered for radical surgery, only 1 died of the disease after a median follow-up of 15 months. CONCLUSION Elective ureteroscopic holmium:yttrium-aluminum-garnet laser ablation of UTTCC is a safe and effective treatment for a select group of patients. In our institution, patients with normal functioning contralateral kidneys are considered for endoscopic treatment and follow-up of their disease if disease is found to be of low grade and volume. Inadequacies in the staging of UTTCC mean that this may, in some cases, turn out to be suboptimal management, and therefore we maintain a low threshold for recommending radical surgery. For another group of patients with single kidneys, global renal dysfunction, or severe comorbidity, endoscopic treatment can prove a valuable palliative option even in those persons who have a large tumor bulk or relatively rapid disease recurrence.

Use of p53 in the diagnosis of upper-tract transitional cell carcinoma

OBJECTIVES To assess the usefulness of p53 staining of cytology specimens obtained ureteroscopically in the diagnosis of upper-tract transitional cell carcinoma (TCC). METHODS We collected specimens from 43 patients undergoing a total of 50 ureteroscopic procedures for a variety of indications, including the diagnosis of TCC. Specimens were obtained by direct biopsy with forceps or basket whenever possible. We examined specimens for evidence of TCC by cytospin as well as cell block for any visible fragments. Each specimen was then stained for overexpression of p53 by immunohistochemical staining, and the degree of staining was graded. Eight patients subsequently underwent nephroureterectomy; the pathologic specimens were stained for p53 and compared with the cytology results. RESULTS Staining for p53 was positive in specimens from 36 of 50 procedures, including all 28 with ureteroscopic or cytologic evidence of TCC (P < 0.0001). By contrast, cytology accurately diagnosed only 23 of the 28. Specimens from all 14 procedures that were negative also stained negative for p53. Specimens from all 8 procedures with no tumor seen and atypical cytology stained positive for p53; 4 of 5 patients with adequate follow-up have had a tissue diagnosis of TCC at that site. Overall, 35 of the 36 specimens that stained positive for p53 were obtained from patients with some history of TCC (P < 0.0001). No significant association could be found between degree of staining and grade (P = 0.3034). The degree of staining of ureteroscopic biopsy specimens was identical to that of the nephroureterectomy specimen in 6 of 8 cases. CONCLUSIONS p53 nuclear protein staining of cytology specimens obtained ureteroscopically appears to correlate well with the presence of upper-tract urinary TCC. Further study is needed to determine if it can provide a definitive diagnosis in cases with indeterminate cytologic findings.

Audit of safety, efficacy, and cost-effectiveness of local anaesthetic cystodiathermy

INTRODUCTION The aim of this study was to audit our experience of cystodiathermy under local anaesthetic (LA) at the time of flexible cystoscopy for recurrent superficial bladder transitional cell carcinoma (TCC). PATIENTS AND METHODS A total of 264 flexible cystoscopies were performed on patients with a past history of TCC. The number and site of recurrences were recorded and selected patients were offered cystodiathermy. Patient tolerability was noted. At follow-up, any recurrence was recorded. RESULTS Eighty patients (30%) had 91 procedures showing one or more recurrences. Fifty-one of the 80 patients (64%) were treated with cystodiathermy under LA. All completed treatment. Forty-five (88%) tolerated the procedure well. Forty-seven (92%) treatments were completed within 5 min. At a median follow-up of 15 weeks, 30 (59%) treated patients had no recurrence and three (6%) had recurrence at the site of treatment. CONCLUSIONS LA cystodiathermy is an effective and well-tolerated alternative to general anaesthetic cystodiathermy that enables treatment at the time of detection and may, thereby, reduce patient anxiety.

The management of ureteric stones

The earliest observations that acoustic shockwaves could fragment brittle materials were made in the 1950s. The first experience of treating renal calculi in humans using extracorporeal shockwave lithotripsy (SWL) was reported in 19801 and by 1983 the first commercially-produced lithotriptor was available, the Dornier HM-3. Its use quickly became wide-spread and it revolutionised themanagement of urinary stone disease from what had previously been entirely surgical to what has become almost exclusively minimally invasive. Although stone fragmentation rates were impressive, treatment with the HM-3 required general anaesthesia. The development of second-generation lithotriptors allowed local anaesthetic treatment but at the cost of less efficient stone fragmentation. Outcomes of treatment with the most contemporary fourth generation lithotriptors approach those of the HM-3, but as an out-patient procedure with oral or intravenous analgesia.2 Today, approximately 80% of all upper tract urinary stone disease is treated with SWL. This topic has been a perennial discussion point amongst urologists; although the latest guidelines have suggested that the stone-free rates for ureteroscopy are higher than with extracorporeal shockwave lithotripsy (ESWL), it is well recognised that the evidence base is weak with many of the studies being retrospective, with precious few randomised clinical trials. This controversy is well argued on both sides by the two sets of authors who are eminent in the field of ureteric stone treatment. However, for the practicing urologist, the decision-making process is not always so straightforward and the decision to intervene must be based not only on the clinical situation faced by the patient, but also by the level of resource available locally. The EAU Guidelines (2008) suggest that 98% of stones 15 mm); (ii) impacted stones; (iii) unfavourable anatomy; and (iv) those in whom two sessions of ESWL have failed to achieve successful fragmentation (T Knoll et al. EAU Update Series 3, 2005). In these scenarios, intervention in the form of ureteroscopy is to be preferred, whilst, in the mid-ureter, the options are equal given the issues in respect of locally available resources and expertise. In the distal ureter, traditionally ureteroscopy is the modality of choice due to the ease of access, high stone-free rates and minimum of complications.