Urinary Tract
Fig. 15.32 Atypical urothelial cells with moderately enlarged, fairly uniform
nuclei containing small nucleoli. The pattern is consistent with mild-to-
moderate urothelial dysplasia of bladder (Papanicolaou x MP).
significantly thickened, the diagnosis is made by evaluating the
cytologic features, and therefore, there is no well-differentiated
or grade I nonpapillary carcinoma. Most in situ transitional cell
carcinomas, by definition, are high grade, as are most infiltrating
nonpapillary carcinomas. Grossly, these carcinomas are often
ulcerated, nodular, or bulky and infiltrate the bladder wall. His-
tologically, the tumors are composed of irregular nests, sheets,
and cords of cells with enlarged, irregular, hyperchromatic
nuclei and relatively scant cytoplasm. Undifferentiated small cell
forms are also seen. Glandular and squamoid components may
be included but, as described later, may also occur in a pure form.
Lymphatic infiltration is common.
Because of the correlation of the cell type and degree of
differentiation to the depth of infiltration, the probability of
such infiltration may be anticipated not only by examination
of biopsy specimens but also by the cytologic findings in these
tumors. The correlation of the grade and pathologic stage based
on the examination of radical cystectomy specimens is shown
in Table 15.2.37
The nonpapillary urothelial carcinomas in this series are of a
higher grade, but whether the tumors are papillary or nonpapil-
lary, the depth of invasion is directly related to the grade. Muscle
invasion, either superficial (P-2) or deep (P-3A), was observed
only in grade II or less-differentiated tumors, and deep invasion
with extension into perivesical tissues (P-3B and P-4) is largely
restricted to poorly differentiated, grade III carcinomas.
In this same group of cases, the cytologic findings in turn
closely correlate with the grade of the tumor. Only 5 of 16 grade
I papillary carcinomas could be classified as positive, but 75%
of grade II and 81% of grade III transitional cell carcinomas were
definitely identified as cancer and furthermore, in all instances,
as carcinomas of a medium or high grade. This permits a predic-
tion of the probable extent of invasion (Table 15.3).
The cytologic findings in voided urine and bladder washings
from patients with invasive transitional cell carcinoma are simi-
lar for high-grade papillary tumors and for nonpapillary tumors
except for less frequent clustering in the latter. It is exceptional
to find only few malignant cells (see Table 15.1). The urine
cellularity is greatly increased, and in most cases, more than
one-fourth of the cells present are neoplastic. The tumor cells
contain large (75-90 pm2), irregular, and pleomorphic nuclei
Fig. 15.33 Poorly differentiated (grade III) urothelial carcinoma.
Considerable nuclear pleomorphism and hyperchromasia are seen. The
nucleocytoplasmic ratio is high (Papanicolaou x MP).
that are hyperchromatic, have a coarsely granular chromatin
pattern, and contain multiple nucleoli or macronucleoli (Figs
15.33 to 15.36). Even if poorly differentiated, the transitional
cells still retain some of their morphologic characteristics.
A judgment of the degree of nuclear enlargement and
pleomorphism permits an evaluation of the probable grade of
the tumor. Reports may be worded "malignant urothelial cells
present—consistent with high-grade, ulcerated transitional cell
The sensitivity of urine cytology for these tumors is high, and
the described morphologic differences from normal and reactive
cells can be readily resolved in most cases.5 If glandular or squa-
mous components are included in the tumor, cells indicating
these changes may be present. Cells from urothelial carcinoma
usually have a homogeneous cytoplasm,31 but vacuolation may
be present and does not necessarily indicate glandular differentia-
tion. Transitional cell carcinomas with clear cell features do occur
and are difficult to distinguish from clear cell adenocarcinomas.38
A cytologic diagnosis of adenocarcinoma should be made only
if cell clusters with well-defined outlines, glandular structures, or
unequivocally columnar-type malignant cells are present.
M onitoring of Patients
Cytologic monitoring of urine is especially helpful in the follow-
up of patients with known and previously conservatively treated
bladder tumors. Low-grade papillary tumors rarely progress to
more aggressive forms but may be associated with dysplasia or
carcinoma in situ and concurrent or subsequent aggressive non-
papillary tumors. Positive cytologic findings in patients whose
biopsy specimens show low-grade papillary tumors are charac-
teristic of such a process. At first presentation, 90% of patients
with invasive carcinoma have such tumors,39 but this is often
associated with the simultaneous presence or a previous occur-
rence of low-grade tumors.
Monitoring of patients by other methods (see sections Special
Techniques and Diagnostic Accuracy) such as flow cytometry has
proved to be of particular value and is slightly more sensitive but
also slightly less specific than urine cytology. Badalament and
co-workers demonstrated this in a series of cases.13 The highest
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