LOCALIZATION UROTHELIAL MICHAEL FUAD
From the Division of Urology, Department Stanford University School of Medicine, Stanford, California
ABSTRACT - The importance of urinary cytology in the localization of urothelial carcinoma is discussed in the light of a case report, and a method to localize the site of a covert malignancy is presented.
The usefulness of exfoliative cytology in the initial diagnosis and subsequent assessment of urothelial transitional cell carcinoma, first demonstrated by Papanicolaou and Marshall’ more than thirty years ago, has been clearly documented in many reports.2-5 The development of its role as a primary diagnostic tool, when radiographic or endoscopic means of demonstrating a neoplastic lesion have failed, has been found to be of equal importance.‘,6-8 We recently had occasion to study a patient in whom the only consistently reliable diagnostic modality was urinary cytology. The purpose of this report is to reemphasize the use of urinary cytology in the diagnosis and management of urothelial neoplasia, to suggest a means by which the source of positive neoplastic cells may be localized, pointing out some potential pitfalls in the methodology employed, and to review the possible existence of morphologic distinctions between the exfoliated cells from frankly invasive urothelial neoplasia and those from carcinoma in situ. Case Report Asymptomatic “cloudy urine” developed in a seventy-two-year-old Caucasian male three months prior to admission. His internist noted microscopic hematuria; there was no evidence of infection.
Intravenous urogram demonstrated a narrow upper pole infundibulum with nondescript irregularity of the middle pole calyces on the left and an entirely normal right kidney and collecting system (Fig. 1). Left retrograde pyelogram demonstrated the same abnormalities. Findings on endoscopic examination of the bladder were negative. Urinary cytologic study from the left collecting system was positive for malignant cells. No cytologic data from the right collecting system or the bladder were collected. On referral to Stanford Medical Center three months later, repeat intravenous urogram and retrograde studies were unchanged, and result of endoscopy was again negative. Because of these nondiagnostic findings, and the persistence of positive voided urine cytology, we thought it necessary to localize the source of neoplastic cells to recommend a rational therapeutic course. The method initially used was similar to that previously described by Stamey, Govan, and Palmer9 for bacterial localization. After catheterization and collection of bladder urine, the bladder was washed with 500 ml. of normal saline, and then a barbotaged sample of “washed bladder” cells was obtained. A 6 F polyethylene ureteral catheter was then passed to the pelvis of each kidney, and separate samples were collected, first by urine drainage collection and then by barbotage with 2 to 3 ml.
FIGURE 1. (A) Intravenous urogram demonstrating narrow upper pole infundibulum and nondescript irreeularitu of middle calux on left. Note left ureter is normal. (B) Close-up view of kidneys demonstrating narF-owing”of-upper pole Lfundibhum on le$.
aliquots of normal saline till a total volume of 30 ml. was obtained from each side. Separate syringes were used throughout. The ureteral catheters were then withdrawn, and random biopsies of the bladder and prostatic urethra were taken with the resecting loop. Results of these collections did not permit localization of the source of tumor cells (Table I). In view of the possible multicentricity of carcinoma in situ and the absence of a distinct radiographic diagnosis, it appeared possible that we might be faced with a rather diffuse, bilateral neoplastic process. The futility of therapy for such a diffuse lesion, however, prompted our consideration of other factors that might explain the results in this initial study. In barbotaging each collecting system, a common reservoir of saline was used. Thus, cells from the left collecting system may have contaminated the saline and barbotaged sample from the right collecting system. In addition, common staining solutions were used to process each slide. Conceivably positive cells from one slide may have washed onto an adjacent negative slide. Finally, our localization method may have permitted ureteral catheter contamination. These considerations led to a second attempt at localization, this time in somewhat modified form. A “catheterized bladder” urine was obtained. Each ureter-al orifice was then occluded by a 8 F bulb-tip ureteral catheter, the bladder was
washed with 500 ml. of normal saline, and a “washed bladder” barbotaged sample was obtained. With the bulb-tip ureteral catheter in place on the left, a 6 F polyethylene ureteral catheter was then introduced into the right renal pelvis and drainage and barbotaged samples were obtained. Leaving the catheter in place on the right, the bulb-tip catheter on the left was then withdrawn and a 6 F polyethylene catheter was introduced to collect drainage and barbotage samples from the left collecting system. Both ureteral catheters were left indwelling for twenty-four hours and were then removed without untoward effect, Results of the second study clearly localized the source of neoplastic cells to the left collecting system (Table I).
Results of collections
Catheterized bladder Washed bladder Right kidney urine Right kidney barbotage Left kidney urine Left kidney barbotage Bladder biopsy Prostatic urethral biopsy
+ + Atypical + + + -
Localization 2 + + + 0 0
FIGURE 2. (A) Microscopic section of renal pelvis showing carcinoma in situ. (B) Microscopic upper ureter showing invasive transitional cell carcinoma.
On the basis of these findings, a left nephroureterectomy was performed. Gross examination of the collecting system disclosed a number of plaque-like or cobblestone lesions in the renal pelvis and the proximal and distal 2 cm. of ureter. The upper pole infundibulum had a somewhat thickened wall, but no exophytic tumor was seen. Microscopic examination of the renal pelvis disclosed carcinoma in situ (Fig. 2A). The upper ureter 1 cm. distal to the ureteropelvic junction contained a grade IV transitional cell neoplasm that invaded the muscularis (Fig. 2B). In addition, invasive tumor was seen in areas of pyelitis cystica. The lower ureter exhibited severe atypia. The patient’s postoperative course was uneventful. Since discharge, voided urine cytologic studies have been negative. Comment Several questions were posed in the present case study. First, in the absence of a morphologically demonstrable lesion, could positive exfoliative cytology be used to localize a neoplastic site and determine an appropriate course of therapy? Second, in the face of both carcinoma in situ and invasive transitional cell, the latter of which had been completely unsuspected, could exfoliative cytology have been used to distinguish between carcinoma in situ and invasive transitional cell carcinoma? Third, what was the significance of exfoliative cytology in upper tract lesions? Ever since Papanicolaou and Marshall’ rekindled interest in the usefulness of exfoliative urinary cytology, numerous reports have ap-
peared, describing a role for the examination of urinary sediments in the diagnosis and followup of urothelial neoplasia.3-6Jo Such reports have been concerned both with correlating the grade and stage of tumor with the reliability of cytologic diagnosis as well as determining the usefulness of the technique in different areas of the urinary tract. In bladder neoplasia urinary cytology has been most reliable for diagnosing high-grade, high-stage lesions.3-5*“,‘2 The incidence of false negative readings in such instances has ranged between 10 to 15 per cent.4,5,7,” In contrast, low-grade, noninvasive tumors have produced a far greater percentage of false negative urinary cytology: low-grade lesions have yielded 60 to 85 per cent false negatives;4,5 noninvasive lesions have led to 50 to 75 per cent false negatives.4,” In most such reports cells that were thought to represent low-grade, noninvasive lesions were usually associated “with few cellular abnormalities and scanty exfoliation”3 and could be diagnosed only when “fragments of the tumor were present in the smears”* Attempts to improve the diagnostic accuracy and yield of exfoliative cytology in lower tract lesions have concentrated on the use of bladder washings and barbotage specimens rather than voided urines. It was readily shown in several studies that such maneuvers would convert a significant number of false negative samples to true positives. 11,13 Application of these observations to upper tract lesions has produced similar results. Insofar as a lesion may be demonstrable radiographically, the use of cytology as an adjunct to diagnosis is well documented.14-l6 More impressive, however, is its use in those instances
in which no lesion can be defined by radiologic or endoscopic means. ~3,~’The literature documenting the successful use of cytology in upper tract lesions is sparse; studies correlating grade of lesion with accuracy of cytologic diagnosis have not been done. Recent attempts of several investigators to obtain improved upper tract exfoliative samples attests to the increasing importance of cytology as a primary tool in the documentation of upper tract neoplasia. l4 The present patient demonstrates one aspect of the need for further attention to upper tract cytology. The passage of consistently positive cells in voided urines assured the presence of a neoplastic lesion; however, the absence of clearcut radiologic or endoscopic findings precluded ready identification of this lesion. Since any site in the urothelium might have been the source of the neoplastic cells, the only therapy that could conceivably be offered would be surgical extirpation of a specific site if it could be localized. We encountered several pitfalls, however, in our initial attempts at localization. Through our use of methods routinely employed in bacterial localization in which colony counts often play a prominent role in clinical interpretation9 we exposed ourselves to the possibility of specimen contamination. In localization for neoplasm even a single neoplastic cell is cause for concern; hence, our use of specific ureteral occlusion prior to separate collections was obviously a mandatory modification. In addition, our initial localization results demonstrated the need in such studies of maintaining separate reservoir as well as syringes for barbotage, and of processing the slides in separate staining solutions. Differences between the two methods we used are readily apparent from their results (Table I). Based on these results, we were able to recommend therapy with the assurance that surgery might be expected to provide a cure for this patient. A new dimension was added to the use of exfoliative cytology when it was recognized that the diagnosis of carcinoma in situ could be correlated with the presence of specific neoplastic cells in the urine. f*2,6,18-21The desquamative nature of neoplastic cells in this lesion’ has provided a significant reliability to the use of cytology in diagnosing this lesion, expecially since there may be no radiographic findings associated with carcinoma in situ, and endoscopic findings often are minimal. In the present patient surgery was performed with a presumptive diagnosis of carci-
noma in situ of the left collecting system. The later finding of an invasive transitional cell carcinoma of that system indicated the need for a retrospective reappraisal of the various samples of positive cells in the various urine samples to determine whether any morphologic distinction between these entities could have been made prospectively. Earlier studies by Malamed et ~1.’ had described a number of apparent differences between the exfoliative cytologies from frank transitional cell carcinoma and carcinoma in situ. According to these workers, the exfoliated cells from invasive carcinomas were characterized by “bizarre nuclear and cytoplasmic configuration with marked individual variation. Nuclei were densely hyperchromatic, enlarged, and irregular in outline. There were prominent nucleoli . . . and scanty, poorly preserved and irregular cytoplasm.“’ In contrast, cells from carcinoma in situ had abundant, well-differentiated cytoplasm and were without the marked variations in cancer cell morphology characteristic of frankly invasive carcinoma. l1 Careful review of the cells obtained from the present patient failed to demonstrate any characteristics that might distinguish frank carcinoma versus carcinoma in situ as their sites of origin. Different populations of cells could not be clearly described, even when barbotage samples were examined. Thus, preoperative distinction between in situ carcinoma or invasive carcinoma in the present patient was, and would have been, impossible. In summary, a method of using urinary exfoliative cytology to localize a site of carcinoma of the urinary tract is described and its potential pitfalls discussed. Use of cytology to distinguish between carcinoma in situ and frankly invasive carcinoma was not possible. Additional methods to render such a distinction possible await further investigation.
Addendum The negative cytologic results reverted to positive eight months later, after four consecutive negative results. A repeat localization, using the same method, demonstrated normal cells from the right collecting system and malignant cells from the bladder. This finding reaffirms our impression that the first localization permitted contamination of right kidney urine by malignant cells from the left.
Stanford, California 94305 (DR. FREIHA)
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