PART TWO
Diagnostic Cytology
indeed the case, and the positive yield in screening programs
for high-risk groups ranges from 10 to 70 per 1000 persons. The
yield is only 2 per 1000 individuals in a bilharzial population
and 10 per 1000 in phenacetin users but still exceeds that in a
routinely screened clinic or hospital population. Screening pro-
grams clearly lead to detection of bladder cancer at a stage earlier
than that in patients who present with symptoms in unscreened
groups, provided that the screening procedure is applied fre-
quently enough. Nevertheless, existing evidence does not estab-
lish that treatment based on early detection of bladder cancer in
screened populations increases the overall length of survival.10
Examination of Symptomatic Patients
The most common presenting symptom in patients with blad-
der cancer is gross hematuria. Patients with gross or microscopic
hematuria must be further evaluated until the source of the
bleeding has been securely established. This may require an
intravenous pyelogram, computed tomography, or magnetic
resonance imaging study because of the possibility of renal ade-
nocarcinoma. Cytologic examination of the urine is indicated in
these cases, and depending on the findings, it may be followed
by bladder washings for flow cytometry, cystoscopy, and blad-
der biopsies. Cytologic examination of voided urine is a simple,
noninvasive procedure with high sensitivity for nonpapillary
and in situ urothelial carcinoma and should be performed in
all symptomatic patients. If combined with DNA ploidy meas-
urements and immunohistochemical studies, the sensitivity
exceeds 80% even for low-grade papillary tumors.11,12
Follow-Up after Treatment
Urine cytology is of particular value in the follow-up of patients
with known and treated urothelial tumors. Low-grade papillary
tumors, whether they are primary or recurrent, cannot be readily
diagnosed cytologically but bladder tumors of grade II or III and
all in situ and nonpapillary carcinomas can be diagnosed with a
high degree of accuracy. These are the significant bladder cancers
that frequently recur or may be associated with low-grade papillary
tumors. Cystoscopy and biopsy are the appropriate procedures
Fig. 15.1 Urothelial and squamous cells in normal voided urine. Cytospin
preparation (Papanicolaou x LP).
for visible tumors, but cytology has the distinct advantage of
sampling the entire urothelial mucosa. This permits detection
of clinically occult and in situ urothelial tumors. Most patients
with superficial nonpapillary bladder carcinoma develop clini-
cally apparent recurrent carcinoma; yet only 40% have positive
urine cytology results immediately after transurethral resection
and before clinically apparent and documented recurrent blad-
der cancer.13 This may be because of inflammation and regen-
erative epithelial atypia in the immediate postoperative period,
which may mask minimal cytologic evidence of carcinoma. If
recurrence follows positive postoperative cytologic findings, it
can be assumed to arise from residual neoplastic epithelium.
Recurrence after negative postoperative cytologic findings sug-
gests transformation within an unstable urothelium and is
often multicentric. Many of the currently available markers for
carcinoma such as bladder tumor antigen, NMP22, fibrin deg-
radation products, telomerase, in situ hybridization, and flow
cytometry appear to have an advantage over urine cytology in
terms of sensitivity. However, most markers tend to be less spe-
cific than cytology, yielding more false-positive results, accord-
ing to Bassi et al.7 The simplicity, convenience, and relative
accuracy of cytologic study of voided urine make it the first-line
diagnostic technique.
Sampling Techniques
Sample collection
Voided urine is the specimen of choice for all screening programs
and for diagnostic studies of male patients because of the ease
of collection and satisfactory results. Catheterized urine is the
preferred specimen from female patients. Hydration of patients,
collection of the second voiding in the morning, and collection
of three successive morning specimens have been recommended
by some investigators, but because of the good cellularity that
can be uniformly obtained by filtration or cytocentrifugation
preparations as shown in Fig. 15.1 and the significant exfolia-
tion from all nonpapillary tumors of the urothelium, examina-
tion of a single urine specimen is sufficient. What is important
is prompt fixation, which can best be accomplished by collec-
tion of 50-100 mL of urine in an equal amount of 50% alco-
hol. Ethyl alcohol is preferable, but isopropyl or denatured
alcohol is acceptable. If the specimen is to be processed by the
Saccomanno blending technique, 2% polyethylene glycol (Car-
bowax) must be added. Urothelial cells remain well preserved
for processing for several days, regardless of whether the urine
is collected after hydration, during the morning hours, or later
during the day. Urine osmolality does not significantly influence
cell preservation,14 but a low pH is desirable and ingestion of
1 g of vitamin C at bedtime before examination has been recom-
mended, although not practical for screening purposes.
Bladder Washings
Bladder washings with normal saline or Ringer's solution per-
formed at cystoscopy, if indicated in combination with biopsies
or resections, produce a highly cellular specimen that contains
more cell clusters and more large, superficial cells than are seen
in voided urine. This procedure is recommended whenever
cystoscopy is performed and is the specimen that should be
used for flow cytometric studies. The washings should also be
collected in equal amounts of alcohol for fixation.
410
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