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Pathology Patterns Reviews
The Cytologic Diagnosis of Low-Grade Transitional Cell
Carcinoma
Jonathan H. Hughes, MD, PhD,1 Stephen S. Raab, MD,2 and Michael B. Cohen, MD3
Key Words: Urinary cytology; Transitional cell carcinoma; Urothelial carcinoma; Tumor markers; Nuclear matrix proteins; Fibrin degradation
products; Bard test
Abstract
Current theory suggests that transitional cell
carcinoma (TCC) occurs as either of 2 disease
processes, each of which has a distinct cytologic
appearance and clinical course: low-grade and highgrade TCC. Urinary cytology has become a mainstay
technique for monitoring disease recurrence in patients
with TCC. Most cases of high-grade TCC can be
diagnosed accurately in urinary cytology specimens.
However, the cytologic diagnosis of low-grade TCC is
difficult; these tumors exhibit subtle cytomorphologic
alterations that are difficult to distinguish from benign
or reactive processes. The cytologic criteria most useful
for diagnosing low-grade TCC in urinary cytology
specimens are reviewed. Additionally, the discussion
includes some of the new ancillary tests that are
emerging as possible diagnostic aids for the detection
of low-grade urothelial neoplasms.
© American Society of Clinical Pathologists
Examination of the urine to detect disease is one of the
oldest clinical laboratory tests known to humans, and references to the art of urinalysis are found in the 6,000-year-old
clay tablets of Sumerian and Babylonian physicians. 1
Hippocrates (460-350 BC) wrote extensively about the value
of examining the urine when assessing the general health of
a patient, and his teachings were validated and expanded as
medicine evolved through the middle ages, the renaissance
period, and into the early modern period.1 Until the 19th
century, urinalysis was used primarily to detect nonneoplastic processes, such as hematuria, bilirubinuria, and crystalluria. In 1864, Sanders reported the detection of tumor
cells in voided urine.2-4 However, this finding was largely
ignored by the medical community until 1945, when Papanicolaou and Marshall advocated the examination of urine
smears to detect cancers of the urinary tract.3,5 Since that
time, the demand for the pathologic evaluation of urothelial
cells in urine specimens has been increasing steadily, and
urine cytology has become a mainstay technique for monitoring disease recurrence in patients with a history of transitional cell carcinoma (TCC) of the urinary tract.1,3,6-15
Despite its 6,000-year history and current widespread
use in modern-day urology practice, urinary cytology
engenders considerable controversy and apprehension in the
pathology and urology communities. While there is general
agreement that urine cytology allows for the detection of
most high-grade, potentially aggressive bladder neoplasms,
the cytologic diagnosis of low-grade TCC is more problematic and controversial.3,9,16-19 There is generalized disagreement about the accuracy of cytologic examination for diagnosing low-grade TCC. Moreover, experts disagree about
which cytologic criteria are most useful for distinguishing
low-grade TCC from benign reactive processes. The
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perceived limitations of routine cytology for detecting lowgrade TCC have led to a proliferation of different ancillary
tests that are designed to augment the accuracy of routine
cytology or even replace it. However, there is still considerable confusion about how these ancillary tests should be
used in clinical practice and how much value they add to
the cytologic evaluation.
The goals of this article are to review the benefits and
limitations of cytology for diagnosing low-grade TCC, to
identify the cytologic criteria that we have found to be the
most useful for establishing a diagnosis of low-grade TCC,
and to summarize the current status of ancillary tests as
adjuncts or alternatives to urine cytology.
Pathology of TCC
TCC of the urinary tract is a relatively common
disease, with approximately 50,000 new cases diagnosed
annually in the United States. The national death rate is
approximately 10,000 persons per annum.15 In addition,
TCC is 2 to 3 times more common in men than in women.
One of the most important risk factors of TCC in the
United States is smoking. Most transitional cell neoplasms
occur in the bladder, although tumors may arise anywhere
along the urothelial mucosa, including the ureters, renal
pelvis, and urethra.20 Current theory suggests that TCC
may occur as either of two distinct disease processes, each
of which has a distinct cytologic appearance and distinct
clinical course: low-grade TCC and high-grade TCC.15 The
majority of TCCs are low-grade tumors. These tumors have
a papillary growth pattern and rarely develop invasion or
metastasize. As a consequence, they are biologically indolent and associated with long survival rates. Cytologically,
most papillary TCCs are low-grade and may be difficult to
distinguish from normal or reactive urothelial cells in
voided urine specimens or bladder washings. High-grade
TCCs exhibit a flat or nodular growth pattern with a high
likelihood of invasion and metastasis. Not surprisingly,
these tumors are associated with poor survival rates. The
cytology of these tumors is almost always high grade.1113,15,16 Some of the fundamental pathologic and clinical
❚Table 1❚❚
Characteristics of Transitional Cell Carcinomas
differences between superficial and invasive TCC are
summarized in ❚Table 1❚❚.
Cytology of TCC
Most cases of high-grade TCC can be diagnosed accurately by the practicing pathologist. These lesions are characterized by malignant cells with pleomorphic angulated
nuclei, markedly increased nuclear/cytoplasmic (N/C) ratios,
and coarse chromatin. There is good interobserver concordance among pathologists for diagnosing high-grade TCC,
and the sensitivity and specificity of urine cytology for highgrade TCC are approximately 95% and 100%, respectively.11-13,16
The cytologic diagnosis of low-grade TCC is more
problematic. These tumors exhibit subtle cytomorphologic
alterations that are difficult to distinguish from benign or
reactive processes ❚Table 2❚❚. This unfortunate circumstance
is confounded by the fact that low-grade lesions do not shed
cells as readily as high-grade lesions, thereby resulting in a
small amount of material on which the pathologist must
base the diagnosis.10,12,13,16 The difficulty that pathologists
have in diagnosing low-grade TCC is reflected by the wide
variation in diagnostic accuracy reported in the published
literature, with a sensitivity ranging between 0% and
73%.3,9,16-19 Part of this wide range in diagnostic accuracy is
due to disagreement among authors about which cytologic
criteria are most important for establishing a diagnosis of
TCC. Reported features indicative of malignancy include
nuclear enlargement, eccentrically placed nuclei, granular
nuclear chromatin, irregular nuclear borders, homogeneous
cytoplasm, absence of nucleoli, irregular papillary fragments, atypical single cells, and cell clusters with peripheral
palisading.6,7,9,11-13,15-24 While most of these studies attempt
to assign a relative importance to each criterion, there have
been few rigorous statistical analyses to assess the usefulness of these criteria for diagnosing TCC.
It is important to recognize the contributions of others in
this area who have toiled before us. Two, in particular, are
noteworthy: Kern and Murphy. In a seminal article published
in 1975, Kern17 reported on qualitative and quantitative
Superficial
Invasive
❚Table 2❚❚
Nonneoplastic Lesions and Conditions That May Be Confused
With Low-Grade Transitional Cell Carcinoma
Approximately two
thirds of tumors
Papillary
Low grade
Low stage
High recurrence rate
Low progression rate
Low mortality
Approximately one
fourth of tumors
Sessile
High grade
High stage
Not applicable
High progression rate
High mortality
Urolithiasis
Bladder instrumentation and catheterization
Immunotherapy
Chemotherapy, topical and systemic
Radiation
Renal epithelial fragments
Diversions and conduits
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© American Society of Clinical Pathologists
Pathology Patterns Reviews
features of TCC as identified in cytologic specimens. The
1984 article by Murphy et al16 articulating the cellular
features of TCC, particularly low-grade TCC, also should be
viewed as a landmark in this field. Our contribution refines
their work.
Key Cytologic Features for Detecting
Low-Grade TCC
As a result of frustration in identifying the salient cytologic criteria, in 1994 Raab et al25 published a study that
used stepwise logistic regression analysis to determine the
cytologic features that are most useful for separating lowgrade TCC from benign processes. Eighty-two bladder wash
specimens, which included 33 low-grade TCCs and 49
nonneoplastic lesions, were reviewed retrospectively. Two
cytopathologists (S.S.R. and M.B.C.) who had no knowledge
of the original cytologic or corresponding histologic diagnoses reviewed the cases and scored them for the presence or
absence of 20 cytomorphologic criteria. The features chosen
have been described as useful in the separation of low-grade
TCC from benign urothelium, including reactive and reparative conditions (“atypical”). These criteria were as follows:
(1) the presence of cell clusters or groups of 5 or more cells;
(2) individual cells, other than superficial cells, present in
sufficient numbers to be observed in most high-power fields;
(3) high cellularity, ie, cells present in most high-power
fields; (4) acute inflammation; (5) increased N/C ratios, ie,
greater than 1:3 to 1:4 (normal, approximately 1:5), in cells
❚Image 1❚ Low-grade transitional cell carcinoma. Cytocentrifuged preparation of a bladder wash specimen. These
tumor cells demonstrate the primary key cytologic criteria
of increased nuclear/cytoplasmic ratio, nuclear irregularity,
and cytologic homogeneity (Papanicolaou, ×400).
© American Society of Clinical Pathologists
other than superficial cells; (6) nucleoli; (7) granular nuclear
chromatin; (8) hyperchromatic nuclear chromatin; (9) open
nuclear chromatin; (10) irregular nuclear borders; (11)
nuclear molding; (12) nuclear eccentricity; (13) elongated
nuclei or spindle-shaped nuclei; (14) necrosis; (15) anisonucleosis; (16) cytoplasmic homogeneity; (17) prominent
nucleoli; (18) irregular border fragments of cell clusters; (19)
absent cytoplasmic collars; and (20) peripheral palisading in
cell clusters.
The presence of individual cells was the only cytologic
feature found in more than 90% of the patients with malignant
disease. Only 3 cytologic features (nuclear molding, necrosis,
and anisonucleosis) were seen exclusively in patients with
malignant disease; however, in most of the patients, these
features were not present. By using a stepwise logistic regression analysis, 3 cytologic features were identified as useful for
discriminating between low-grade TCC and nonneoplastic
lesions.26,27 These features were increased N/C ratios, irregular
nuclear borders, and cytoplasmic homogeneity ❚Image 1❚❚
through ❚Image 6❚❚.
The numbers of patients with benign and malignant
disease in whom these criteria were observed are shown in
❚Table 3❚❚. In 15 patients (45%) with malignant disease, all 3
cytologic criteria were present; and in 27 patients (82%), at
least 2 of the criteria were present. The contingency table
sensitivity, specificity, positive predictive value, and negative
predictive value for the diagnosis of low-grade TCC using the
3 combined cytologic criteria were 45%, 98%, 94%, and 73%,
respectively ❚Table 4❚❚. By using the logistic regression model,
the predicted probability of malignancy with all 3 features was
❚Image 2❚ Low-grade transitional cell carcinoma. Cytocentrifuged preparation of a bladder wash specimen. These tumor
cells illustrate the primary key cytologic criteria of increased
nuclear/cytoplasmic ratio and nuclear irregularity. The third key
primary criterion, cytoplasmic homogeneity, is not present
(Papanicolaou, ×400).
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❚Image 3❚ Low-grade transitional cell carcinoma. Cytocentrifuged preparation of a bladder wash specimen. These
tumor cells illustrate the primary key cytologic criteria of
increased nuclear/cytoplasmic ratio and homogeneous cytoplasm. In addition, the secondary criterion of nuclear eccentricity also is present (Papanicolaou, ×400).
❚Image 4❚ Low-grade transitional cell carcinoma. Cytocentrifuged preparation of a bladder wash specimen. These
tumor cells demonstrate the secondary cytologic criteria of
nuclear eccentricity and nuclear hypochromasia, as well as
the primary criterion of increased nuclear/cytoplasmic ratio
(Papanicolaou, ×400).
❚Image 5❚ Low-grade transitional cell carcinoma. Cytocentrifuged preparation of a bladder wash specimen. These
tumor cells demonstrate the key primary cytologic criterion
of cytoplasmic homogeneity, as well as the secondary criterion of nuclear hypochromasia (Papanicolaou, ×400).
❚Image 6❚ Low-grade transitional cell carcinoma. Cytocentrifuged preparation of a bladder wash specimen. These
tumor cells demonstrate the key primary cytologic criteria of
increased nuclear/cytoplasmic ratio, nuclear irregularities, and
cytoplasmic homogeneity. In addition, some of the cells
demonstrate the key secondary criteria of nuclear eccentricity and nuclear hypochromasia (Papanicolaou, ×400).
P = .98. The contingency table sensitivity, specificity, positive
predictive value, and negative predictive value using at least 2
of the 3 cytologic criteria for the diagnosis of low-grade TCC
were 85%, 96%, 93%, and 90%, respectively ❚Table 5❚❚.
The results of our statistical analysis suggest that the
diagnosis of low-grade TCC should be based more on individual cell morphologic features than on architectural aberrations. Features such as increased cell clusters with
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© American Society of Clinical Pathologists
Pathology Patterns Reviews
❚Table 3❚❚
Probability of Low-Grade TCC Based on 3 Cytologic Features
Cytologic Criteria
Increased N/C Ratio
+
+
+
–
+
–
–
No. of Patients
Irregular Nuclear Borders
+
+
–
+
–
+
–
–
—
Total
Cytoplasmic Homogeneity
+
–
+
+
–
–
+
–
—
❚Table 4❚❚
Number of Patients With TCC Predicted by 3 Cytologic
Criteria and Observed by Histology*
Probability of Tumor (%)
94
88
100
100
0
22
29
3
—
Yes
No
Total
Benign
1
1
0
0
3
7
5
32
49
❚Table 5❚❚
Number of Patients With TCC Predicted by at Least 2 of 3
Cytologic Criteria and Observed by Histology*
Histology
Histology
All Cytologic
Features Present
TCC
15
8
4
1
0
2
2
1
33
TCC
Benign
Total
15
18
33
1
48
49
16
66
82
At Least 2 Cytologic
Features Present
TCC
Benign
Total
Yes
No
Total
28
5
33
2
47
49
30
52
82
TCC, transitional cell carcinoma.
* Sensitivity, 45%; specificity, 98%; positive predictive value, 94%; negative
predictive value, 73%.
TCC, transitional cell carcinoma.
* Sensitivity, 85%; specificity, 96%; positive predictive value, 93%; negative
predictive value, 90%.
peripheral cellular palisading and irregular border fragments, although suggested by other authors9,24 as indicative
of malignancy, were not statistically significant in this
study. The 3 key cytologic criteria, if used in combination,
resulted in a relatively low diagnostic sensitivity (45%),
reflecting the overlap of cytologic findings in benign and
malignant conditions. If at least 2 of the key criteria were
present, the sensitivity for detecting low-grade TCC was
85%. This approach allowed for a significant increase in
sensitivity, with only a slight decrease in specificity (98%
with 3 criteria and 96% with at least 2 criteria).
In addition, 2 secondary criteria also were identified that
were culled from the analysis after exclusion of the primary
criteria. These are eccentrically placed nuclei and nuclear
hypochromasia (Images 3 through 6). These additional
criteria are of particular value when only 1 or 2 of the
primary criteria are present. As noted, the ability to identify
the criteria, as well as their frequency, varies somewhat from
case to case. Thus, from a pragmatic standpoint, we used the
primary and secondary criteria in combination when evaluating specimens. It is worth recognizing that these criteria
are essentially the same as those identified by Murphy et al16
a decade earlier when evaluating filter preparations. Thus,
we believe that these criteria are evaluable in urinary specimens prepared by different methods, including filter and
cytocentrifuged preparations, as done in our laboratory. As
yet, we have insufficient experience with the monolayer
technologies that are available. It is likely that the majority of
these criteria should be identifiable with these techniques,
although hypochromasia may be more difficult to appreciate
given the method used.
Our statistical analysis demonstrated that low-grade
TCC can be diagnosed with a high degree of accuracy when
key cytologic criteria are applied. Moreover, in a subsequent
study in which these same criteria were applied prospectively to a new set of urine specimens by a panel of pathologists with varying degrees of experience, Raab et al 28
demonstrated that these key cytologic criteria can be learned
and effectively applied with high accuracy. However, our
studies and those of others also demonstrate that, because of
the cytologic overlap between low-grade TCC and reactive
processes, the sensitivity of cytology for detecting low-grade
TCC is less than 100%. This fact suggests that in a small
proportion of cases, cellular morphologic features alone may
not be predictive of malignant behavior.
In an effort to improve the diagnostic sensitivity for the
detection of TCC, there has been considerable interest in
developing new techniques to augment or replace urine
cytology as a screening test. These techniques, such as image
analysis flow cytometry and fluorescence in situ hybridization,
are generally costly and often not readily available in most
laboratories, including our own.29-36 Many of these techniques
© American Society of Clinical Pathologists
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❚Table 6❚❚
Comparison of FDA-Approved Bladder Tumor Marker Tests
Substance
Measured
Test
Bard Diagnostics
(Redmond, WA) BTA25,36-48
AuraTek (PerImmune,
Rockville, MD, and
Organon Teknika,
Dublin, Ireland) FDP49-52
Matritech (Newton, MA)
NMP2253-58
Type of Assay
Sensitivity for
TCC (%)
Sensitivity for
Low-Grade
TCC (%)
Specificity in
Patients With
Other Urologic
Diseases (%)
Basement membrane
complexes
Fibrin/fibrinogen
degradation products
Latex agglutination
(qualitative result)
Dipstick
(qualitative result)
40-65
17-40
80-95
68
62-64
86
Nuclear mitotic
apparatus protein
Enzyme immunoassay
(quantitative result)
70
Not reported
80
FDA, Food and Drug Administration; TCC, transitional cell carcinoma.
are in different stages of development and have not gained
widespread acceptance, while some, such as image analysis
and flow cytometry, clearly enhance the sensitivity of
cytology for the detection of urothelial neoplasms but are
used routinely only at some institutions. However, these tests,
like cytology, are better at detecting high-grade lesions than
low-grade lesions. Another drawback of these specialized
techniques is that they are relatively expensive and labor
intensive and, thus, may not be suitable for smaller laboratories. In short, while there is value in these ancillary studies,
we do not believe that their cost-effectiveness justifies their
routine use at this time.
Newer Approaches to Diagnosis:
Tumor Markers
Recently, another category of clinical tests has emerged
that may improve the diagnostic accuracy of urine cytology or
perhaps may replace urine cytology. This class of tests is
based on the detection of polypeptides or other macromolecules that are exfoliated into the urine by tumor cells. In
theory, tests based on the detection of exfoliated tumor
markers provide several advantages over conventional
cytology. Because tumor markers can be measured by
immunologically based assay systems, these tests have the
potential to provide an objective quantitative result for the
clinician and eliminate the subjectivity inherent in a cytologic
examination. This quantitative result could be followed up
over time to monitor the patient’s response to therapy or to
detect tumor recurrence. These immunoassays are automated
easily and can be performed in the urologist’s office at the
time of clinical testing or on a large scale in the clinical laboratory, thereby making them potentially less time consuming
and less expensive than cytologic examination. Because all of
these new tests are noninvasive, they also may permit a significant reduction in the frequency of cystoscopic examinations
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for patients undergoing surveillance for recurrent TCC.
Currently, 3 immunoassays based on the detection of tumor
markers in the urine have been approved by the US Food and
Drug Administration: the BTA (bladder tumor antigen; Bard
Diagnostic Sciences, Redmond, WA), FDP (fibrin degradation
product; AuraTek, PerImmune, Rockville, MD, and Organon
Teknika, Dublin, Ireland), and NMP22 (nuclear matrix protein;
Matritech, Newton, MA) ❚Table 6❚❚.
The Bard BTA test is a latex agglutination test that qualitatively detects the presence of basement membrane
complexes in the urine.25,37-46 The specific antigen measured
by the test is composed of basement membrane complexes
that have been isolated and characterized from the urine of
patients with bladder cancer. These complexes are composed
of specific polypeptides that range from 16 to 165 kd. The
Bard test requires minimal technical expertise to perform,
and it may be performed in the physician office laboratory
by persons with minimal technical training. In published
studies of the usefulness of the Bard test for diagnosing de
novo or recurrent TCC of the bladder, the test had a sensitivity of 40% to 65%.37,38,47-49 The specificity of the test was
approximately 95% in healthy individuals with no history of
urinary tract disease and approximately 80% to 95% in
patients with urologic conditions other than bladder cancer
(eg, lithiasis, cystitis, prostatic hyperplasia).37,38,47-49
The AuraTek FDP test is an immunoassay-based
urine dipstick test that detects intact fibrinogen and
fibrinogen/fibrin degradation products.51 The degradation
products have been shown to be elevated in the urine of
patients with malignant neoplasms of the bladder.51,52 In
preliminary studies50 of patients with a history of bladder
cancer, the sensitivity of the FDP test for detecting recurrent TCC was 68%; in the patients with invasive TCC,
the sensitivity was 100%. The specificity of the test was
96% in healthy subjects, 86% in patients with urologic
diseases other than bladder cancer, and 80% in patients
undergoing surveillance for bladder cancer but with a
© American Society of Clinical Pathologists
Pathology Patterns Reviews
negative cystoscopic examination at the time of the
assay. 50 This test is easy to use and ideally suited for
point-of-care testing.
The Matritech NMP22 test uses an enzyme
immunoassay to detect the nuclear mitotic apparatus
protein.53-58 This protein associates with the mitotic spindle
apparatus during mitosis and is thought to be involved with
the proper distribution of chromatids to daughter cells. It also
has been shown to be elevated in the urine of patients with
TCC of the bladder. In preliminary tests to evaluate the
usefulness of the NMP22 assay for detecting recurrent TCC,
the sensitivity of the test was approximately 70%, and the
specificity was approximately 80%. The sensitivity of the
test was almost 100% in patients with invasive TCC.53,54 An
advantage of the NMP22 test over the Bard test and the FDP
test is that it is quantitative, while the Bard and FDP tests are
qualitative. Thus, the NMP22 level can be followed up over
time to assess disease recurrence or response to therapy.
There also is the possibility that additional studies will show
a correlation between the urine NMP22 level and the tumor
histologic grade and/or stage. If such correlations can be
demonstrated, the urine NMP22 level might predict the
extent of disease and permit the stratification of patients into
different surveillance categories. One disadvantage of the
NMP22 assay compared with the Bard BTA test and the
AuraTek FDP test is that it is an enzyme immunoassay assay
rather than a simple latex agglutination or dipstick test; thus,
unlike the BTA and FDP tests, it is not as well suited to
point-of-care testing.
A few general points are worth noting. First, this
approach to the evaluation of patients with suspected TCC is
still being evaluated. While these tests have potential value, it
remains to be determined how they will be used for routine
patient care. Second, given the relatively high sensitivity of
urinary cytology for the detection of high-grade TCC, the
added value of these tests in this setting also remains to be
determined. Third, many of the reported studies have been
multi-institutional, and it is therefore difficult to discern the
reported accuracy of urinary cytology within individual institutions. In addition, in many studies the cytopathologist(s)
involved is unclear. Moreover, the focus has been on voided
urine samples and not bladder wash specimens, and, therefore, comparisons should be done carefully depending on
one’s experience. Fourth, the control group should reflect the
patient population being assessed, eg, patients with
suspected urothelial tumors and not patients without urologic
symptoms and signs. Last, for the diagnosis of low-grade
TCC, the usefulness of these assays is still unknown. While
these tumors account for the majority of TCCs, are associated with the lowest rates of diagnostic accuracy, and cause
most of the anxiety in the evaluation of urinary cytologic
specimens, the value of these newer ancillary tests remains to
© American Society of Clinical Pathologists
be determined even in this setting. The sensitivity of these
assays in low-grade tumors, many of which are noninvasive
or “minimally” invasive (Ta/T1), is not significantly better
than that indicated in some of the published reports of the
accuracy of urinary cytology.
Final Comments: An Approach
In the cytologic evaluation of urinary specimens for
low-grade TCC, we reiterate that we have found key criteria,
both primary and secondary, that seem to be useful prospectively. However, we believe a few additional points are
important. It is worth noting that most of our experience is
based on the evaluation of bladder wash specimens. While
these criteria also have merit in voided urine samples, such
specimens often are hypocellular and admixed with large
numbers of inflammatory cells, which can obscure cellular
details. In addition, our experience is based on the use of
cytocentrifuged preparations. As yet, we have insufficient
experience to comment on the usefulness of these criteria for
evaluating monolayer technologies, such as those from Cytec
(Marlborough, MA) and Autocyte (Burlington, NC).
We have made a concerted effort to produce definitive
urocytologic diagnoses. While we fully recognize that not
all specimens are appropriately categorized as benign or
malignant, we try to distinguish as clearly between these
two options as possible. In this context, cells that are reactive, reparative, or degenerative, for example, have, by and
large, been categorized as benign, or in our terminology,
“No tumor cells identified.” Generally, we have consciously
tried to avoid diagnosing such samples as atypical. Thus, we
have typically diagnosed cells as benign, suggestive of lowgrade TCC, and low-grade TCC. In this regard, it is very
important to specify the grade of the (suspected) tumor, ie,
low or high, since the clinical implications are dramatically
different. For example, the identification of cells that
suggest a high-grade tumor will elicit a different algorithm
by the urologist in the context of cystoscopically visible
papillary tumors than a sessile tumor. Similarly, the concern
for a low-grade tumor based on cytologic examination will
be viewed differently depending on the additional information available to the urologist. Therefore, we believe
strongly that all reports should indicate clearly what the
grade, or suspected grade, of the tumor seems to be.
With respect to microscopic evaluation, a few final
points are noteworthy. Superficial, cap, umbrella, or dome
cells are not part of the neoplastic process. Consequently, we
tend to ignore this cell type when evaluating the specimens.
As stated previously, the key criteria are based on cytologic
detail and not architectural features. Therefore, we generally
have not found it useful to evaluate urothelial clusters for the
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Hughes et al / DIAGNOSIS OF LOW-GRADE TCC
presence or absence of specific criteria. Rather, the evaluation of criteria in single cells or small clusters of cells has
been most useful. Third, while these criteria can be learned,
the approach requires increased attention focused on cytologic details. Finally, it is our hope that the criteria we have
identified and found useful prospectively will be of value to
others in the microscopic evaluation for low-grade TCC and
will increase the accuracy of this diagnosis when it is based
on cytomorphology.
From the Departments of 1Pathology, The University of Iowa
Hospitals and Clinics, Iowa City; 2Pathology, Allegheny
University for Health Sciences, Allegheny General Hospital,
Pittsburgh, PA; and 3Pathology and Urology, The University of
Iowa Hospitals and Clinics and Veteran Affairs Medical Center,
Iowa City.
Address reprint requests to Dr Cohen: Dept of Pathology,
The University of Iowa, 200 Hawkins Dr, 5216C RCP, Iowa City,
IA 52242.
References
1. Haber MH. Pisse prophecy: a brief history of urinalysis. Clin
Lab Med. 1988;8:415-430.
2. Sanders WR. Cancer of the bladder: fragments forming
urethral plugs discharged in the urine: concentric colloid
bodies. Edinburgh J Med. 1864;10:273-274.
3. Rife CC, Farrow GM, Utz DC. Urine cytology of transitional
cell neoplasms. Urol Clin North Am. 1979;6:599-612.
4. Long SR, Cohen MB. Classics in cytology, V: William
Sanders and early urinary tract cytology. Diagn Cytopathol.
1991;8:135-136.
5. Papanicolaou GN, Marshall VF. Urine sediment smears as a
diagnostic procedure in cancers of the urinary tract. Science.
1945;101:519-520.
6. Badalament RA, Gay H, Cibas ES, et al. Monitoring
endoscopic treatment of superficial bladder carcinoma by
postoperative urinary cytology. J Urol. 1987;138:760-762.
7. El-Bolkainy MN. Cytology of bladder carcinoma. J Urol.
1980;124:20-22.
8. Gamarra MC, Zein T. Cytologic spectrum of bladder cancer.
Urology. 1998;23:23-26.
9. Koss LG, Deitch D, Ramanthan R, et al. Diagnostic value of
cytology of voided urine. Acta Cytol. 1985;29:810-816.
10. Maier U, Simak R, Heuhold N. The clinical value of urinary
cytology: 12 years of experience with 615 patients. J Clin
Pathol. 1995;48:314-317.
11. Murphy WM. Current topics in the pathology of bladder
cancer. Pathol Annu. 1983;18:1-25.
12. Murphy WM. Urinary cytology in diagnostic pathology. Diagn
Cytopathol. 1985;1:173-175.
13. Murphy WM. Current status of urinary cytology in the
evaluation of bladder neoplasms. Hum Pathol. 1990;21:886896.
14. Schumann GB. The growing importance of urinary cytologic
testing. Lab Med. 1995;26:801-808.
15. Yazdi HM. Genitourinary cytology. Clin Lab Med. 1991;
11:369-401.
S66
Am J Clin Pathol 2000;114 (Suppl 1):S59-S67
16. Murphy WM, Soloway MS, Jukkola AF, et al. Urinary
cytology and bladder cancer: the cellular features of
transitional cell neoplasms. Cancer. 1984;53:1555-1565.
17. Kern WH. The cytology of transitional cell carcinoma of the
urinary bladder. Acta Cytol. 1975;19:420-428.
18. Esposito PL, Zajicek J. Grading of transitional cell neoplasms
of the urinary bladder from smears of bladder washings: a
critical review of 326 tumors. Acta Cytol. 1972;16:529-537.
19. Shenoy UA, Colby TV, Schumann GB. Reliability of urinary
cytodiagnosis in urothelial neoplasms. Cancer. 1985;56:20412045.
20. Friedell GH, Bell JR, Burney SW, et al. Histopathology and
the classification of urinary bladder carcinoma. Urol Clin
North Am. 1976;3:53-70.
21. Jordan AM, Weingarten J, Murphy WM. Transitional cell
neoplasms of the urinary bladder: can biologic potential be
predicted from histologic grading? Cancer. 1987;60:27662774.
22. Schwalb DM, Herr HW, Fair WF. The management of
clinically unconfirmed positive urinary cytology. J Urol.
1993;150:1751-1756.
23. Umiker W. Accuracy of cytologic diagnosis of cancer of the
urinary tract. Symp Diagn Accur Cytol Techniq. 1964;8:186-193.
24. Kannan V, Bose S. Low grade transitional cell carcinoma and
instrument artifact: a challenge in urinary cytology. Acta
Cytol. 1993;37:899-902.
25. Raab SS, Lenel JC, Cohen MB. Low grade transitional cell
carcinoma of the bladder: cytologic diagnosis by key features
as identified by logistic regression analysis. Cancer.
1994;74:1621-1626.
26. Cohen MB, Egerter DP, Holly EA, et al. Pancreatic
adenocarcinoma: regression analysis to identify improved
cytologic criteria. Diagn Cytopathol. 1991;7:341-345.
27. Prentice RL. Use of the logistic model in retrospective studies.
Biometrics. 1976;32:599-606.
28. Raab SS, Slagel DD, Jensen CS, et al. Low-grade transitional
cell carcinoma of the urinary bladder: application of select
cytologic criteria to improve diagnostic accuracy [published
correction appears in Mod Pathol. 1996;9:803]. Mod Pathol.
1996;9:225-232.
29. Badalament RA, Kimmel M, Gay H, et al. The sensitivity of
flow cytometry compared with conventional cytology in the
detection of superficial bladder carcinoma. Cancer. 1987;
59:2078-2085.
30. Cajulis RS, Haines GK, Frias-Hidvegi D, et al. Cytology, flow
cytometry, image analysis, and interphase cytogenetics by
fluorescence in situ hybridization in the diagnosis of
transitional cell carcinoma in bladder washes: a comparative
study. Diagn Cytopathol. 1995;13:214-224.
31. Attalah AM, El-Didi M, Seif F, et al. Comparative study
between cytology and dot-ELISA for early detection of
bladder cancer. Am J Clin Pathol. 1996;105:109-114.
32. Mao L, Schoenberg MP, Scicchitano M, et al. Molecular
detection of primary bladder cancer by microsatellite analysis.
Science. 1996;271:659-662.
33. van der Poel HG, Witjes JA, van Stratum P, et al. Quanticyt:
karyometric analysis of bladder washing for patients with
superficial bladder cancer. Urology. 1996;48:357-364.
34. Bonner RB, Hemstreet GP, Fradet Y, et al. Bladder cancer risk
assessment with quantitative fluorescence image analysis of
tumor markers in exfoliated bladder cells. Cancer. 1993;
72:2461-2469.
© American Society of Clinical Pathologists
Pathology Patterns Reviews
35. Sagerman PM, Saigo PE, Sheinfeld J, et al. Enhanced
detection of bladder cancer in urine cytology with Lewis X,
M344 and 19A211 antigens. Acta Cytol. 1994;38:517-523.
36. Meloni AM, Peier AM, Haddad FS, et al. A new approach in
the diagnosis and follow-up of bladder cancer: FISH analysis
of urine, bladder washings, and tumors. Cancer Genet
Cytogenet. 1993;71:105-118.
37. Sarosdy MF, DeVere White RW, Soloway MS, et al. Results of
a multicenter trial using the BTA test to monitor for and
diagnose recurrent bladder cancer. J Urol. 1995;154:379-384.
38. Sarosdy MF, Hudson MA, Ellis WJ, et al. Improved detection
of recurrent bladder cancer using the Bard BTA stat test.
Urology. 1997;50:349-353.
39. D’Hallewin MA, Baert L. Initial evaluation of the bladder
tumor antigen test in superficial bladder cancer [published
correction appears in J Urol. 1996;155:2041]. J Urol.
1996;155:475-476.
40. Droller MJ. Improved detection of recurrent bladder cancer
using the Bard BTA stat test. J Urol. 1998;159:601-602.
41. Ellis WJ, Blumenstein BA, Ishak LM, et al. Clinical
evaluation of the BTA TRAK assay and comparison to voided
urine cytology and the Bard BTA test in patients with
recurrent bladder tumors: The Multi Center Study Group.
Urology. 1997;50:882-887.
42. Johnston B, Morales A, Emerson L, et al. Rapid detection of
bladder cancer: a comparative study of point of care tests. J
Urol. 1997;158:2098-2101.
43. Leyh H, Mazeman E. Bard BTA test compared with voided
urine cytology in the diagnosis of recurrent bladder cancer.
Eur Urol. 1997;32:425-428.
44. Schamhart DH, de Reijke TM, van der Poel HG, et al. The
Bard BTA test: its mode of action, sensitivity and specificity,
compared to cytology of voided urine, in the diagnosis of
superficial bladder cancer. Eur Urol. 1998;34:99-106.
45. van der Poel HG, Van Balken MR, Schamhart DH, et al.
Bladder wash cytology, quantitative cytology, and the
qualitative BTA test in patients with superficial bladder
cancer. Urology. 1998;51:44-50.
46. Zimmerman RL, Bagley D, Hawthorne C, et al. Utility of the
Bard BTA test in detecting upper urinary tract transitional
cell carcinoma. Urology. 1998;51:956-958.
© American Society of Clinical Pathologists
47. Kirollos MM, McDermott S, Bradbrook RA. The
performance characteristics of the bladder tumour antigen
test. Br J Urol. 1997;80:30-34.
48. Leyh H, Hall R, Mazeman E, et al. Comparison of the Bard
BTA test with voided urine and bladder wash cytology in the
diagnosis and management of cancer of the bladder. Urology.
1997;50:49-53.
49. Ianari A, Sternberg CN, Rossetti A, et al. Results of Bard
BTA test in monitoring patients with a history of transitional
cell cancer of the bladder. Urology. 1997;49:786-789.
50. Schmetter BS, Habicht KK, Lamm DL, et al. A multicenter
trial evaluation of the fibrin/fibrinogen degradation products
test for detection and monitoring of bladder cancer. J Urol.
1997;158:801-805.
51. Wajsman Z, Merin CE, Chu TM, et al. Evaluation of
biological markers in bladder cancer. J Urol. 1975;114:879893.
52. McCabe RP, Lamm DL, Haspel MV, et al. A diagnosticprognostic test for bladder cancer using a monoclonal
antibody-based enzyme-linked immunoassay for detection of
urinary fibrin(ogen) degradation products. Cancer Res.
1984;44:5886-5893.
53. Carpinito GA, Stadler WM, Briggman JV, et al. Urinary
nuclear matrix protein as a marker for transitional cell
carcinoma of the urinary tract. J Urol. 1998;156:1280-1285.
54. Soloway MS, Briggman JV, Carpinito GA, et al. Use of a new
tumor marker, urinary NMP22, in the detection of occult or
rapidly recurring transitional cell carcinoma of the urinary
tract following surgical treatment. J Urol. 1996;156:363-367.
55. Chen YT, Hayden CL, Marchand KJ, et al. Comparison of
urine collection methods for evaluating urinary nuclear
matrix protein, NMP22, as a tumor marker. J Urol.
1997;158:1899-1901.
56. Grossman HB. New methods for detection of bladder cancer.
Semin Urol Oncol. 1998;16:17-22.
57. Miyanaga N, Akaza H, Ishikawa S, et al. Clinical evaluation
of nuclear matrix protein 22 (NMP22) in urine as a novel
marker for urothelial cancer. Eur Urol. 1997;31:163-168.
58. Shelfo SW, Soloway MS. The role of nuclear matrix protein
22 in the detection of persistent or recurrent transitional-cell
cancer of the bladder. World J Urol. 1997;15:107-111.
Am J Clin Pathol 2000;114 (Suppl 1):S59-S67
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