PART TWO
Diagnostic Cytology
with polysomy is considered positive for cancer. The sensitivity
of this test varies from 55 to 98% and specificity from 55.8 to
100%.87-89
The ImmunoCyt test is a combination of cytology and im-
munofluorescence microscopy, and it requires three fluorescent
monoclonal antibodies, MO.344 and LDQ10, which detect
mucin antigens expressed on most bladder cancer cells but not
in normal transitional epithelial cells, and 19A21, which detects
a high-molecular-weight form of the carcinoembryonic antigen.
The sensitivity of this test varies from 61 to 92% and specificity
varies from 71 to 90%.90,91
Telomerase
Telomerase is not normally expressed in cells. The presence of
telomerase activity may indicate the ability of a cell to bypass the
telomeric "clock" that limits the proliferative capacity of normal
somatic cells and may reflect the presence of immortalized or
cancer cells. Measurements of telomerase activity in exfoliated
cells in the urine may be a helpful marker for detecting bladder
cancer. The standard technique of measuring telomerase activity
is the polymerase chain reaction in the form of telomeric repeat
action protocol which is still in the experimental phase and is
not yet commercially available. In the studies considered, the
sensitivity of telomerase test varies from 46 to 85% and specifi-
city from 24 to 99 %.80,82,92,93
DNA Méthylation
DNA methylation is a key regulator of gene transcription
and genomic stability, and alteration of DNA methylation
is one of the most consistent epigenetic changes in human
cancer. Nakagawa et al. demonstrated progressively increasing
expression of DNA methyltransferase (DNMT) with increasing
grade of transitional cell carcinoma.94 Methylation was associ-
ated with advanced tumor stage, and mortality rates when com-
pared with tumors without methylation.95 Wang et al. found
that DNA profiling distinguishes low-grade papillary urothelial
carcinoma from reactive urothelium in urine.96 Methylation
profiling in the detection of urothelial carcinoma in urine has
been reported by Pu et al.97
Other Tumor Markers
Large-scale gene expression profiling of bladder cancer using
CDNA microarrays has been reported recently and could have
potential clinical utility if applied to cytology.98-100 Currently,
bladder cancers are staged based on tumor-node metastasis
(TNM) criteria; however, molecular markers such as p53 (Fig.
15.58), p21, and p16 will be used increasingly in the future to
identify those patients at highest risk for disease progression.50,101
A novel proteomic approach for biomarker profiling of transi-
tional cell carcinoma has been described.102
For additional information on FISH and other molecular
testing see Chapter 36, Molecular Techniques.
Diagnostic Accuracy
The purpose and goals of cytologic examination of urine were
discussed at the beginning of this chapter. Predictably, the
yield is low in screening programs but is high in the diagnostic
Fig. 15.58 Strong nuclear immunostaining of P53 in urothelial carcinoma
of the renal pelvis (P53 x MP).
evaluation of patients who are symptomatic or who are being
monitored after having been previously diagnosed with and
treated for bladder cancer. The reported results vary considerably
because of differences in the patient population, in the method
of examination, and in the diagnostic criteria and nomenclature
used. All reports of series of bladder tumors indicate that papil-
lomas and well-differentiated papillary carcinomas cannot be
reliably diagnosed unless the cytologic examination is supple-
mented with technically more complex DNA ploidy and histo-
chemical studies. If these tumors are included, the results differ
significantly from those of series confined to invasive bladder
tumors.6 The accuracy also differs between untreated and treated
patients with both low- and high-grade tumors.6 Nevertheless,
the sensitivity for transitional cell carcinoma is high. The over-
all sensitivity of urine cytology for primary carcinoma of the
bladder—namely, the ability to identify correctly patients with
malignant disease as measured by the rate of cytologic diag-
noses in cases of cancer—has been reported to range from 47%
to 97%.7,103,104 The sensitivity in our own cases (Table 15.5) is
84%.
The sensitivity of this examination is not adequate for a diag-
nostic test of papillomas or grade I papillary carcinomas, but
these tumors are for all practical purposes benign. The sensitiv-
ity increases to 80% for grade II and to 94% for grade III urothe-
lial carcinomas. Carcinomas in situ similarly can be diagnosed
as suspicious or positive.
The grade of urothelial tumors is associated with the stage,
and a similar correlation exists between cytologic findings and
the stage of the disease.37 Recurrences relate more to the stage
than the grade and are often characterized by a higher grade than
was noted when the tumor was first diagnosed. Positive results
of urine cytology have been reported to be associated with a
poor prognosis and are a separate risk factor. This is undoubt-
edly because high-grade tumors tend to be more often positive
than low-grade papillary and therefore nonaggressive tumors.
Increased nuclear size and pleomorphism and the greater exfo-
liation in poorly differentiated carcinomas have been docu-
mented by morphometric measurements and account for the
high rate of positive diagnoses in these cases. The nuclear size,
irregular and coarse chromatin pattern, and pleomorphism can
be correlated with the grade of tumors. An exact grade need not
be indicated in a cytopathologic report, but a comment that
the findings are consistent with poorly differentiated, probably
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