Simple, safe, and inexpensive method that may uncoverSimple, safe, and inexpensive method that may uncover
a hidden urothelial cancer.a hidden urothelial cancer.
Primarily used for diagnosis of symptomatic patients.Primarily used for diagnosis of symptomatic patients.
Detection of cancer in high-risk patientsDetection of cancer in high-risk patients
Follow-up of patients with history of urinary tractFollow-up of patients with history of urinary tract
Patients with low-grade noninvasive tumors can bePatients with low-grade noninvasive tumors can be
followed up cytologically.followed up cytologically.
Patients with negative cytologic findings have a very lowPatients with negative cytologic findings have a very low
risk of recurrence.risk of recurrence.
High-grade cytologic abnormalities predict an aggressiveHigh-grade cytologic abnormalities predict an aggressive
tumor coursetumor course
A positive cytology should always be confirmedA positive cytology should always be confirmed
histologically before definitive therapy.histologically before definitive therapy.
False-positive diagnoses are commonly seen in cases ofFalse-positive diagnoses are commonly seen in cases of
stones, chemotherapy, radiation, viruses, reactive orstones, chemotherapy, radiation, viruses, reactive or
degenerative changes, benign prostatic hyperplasia,degenerative changes, benign prostatic hyperplasia,
prostatitis, and pseudopapillary clusters.prostatitis, and pseudopapillary clusters.
False-negative diagnosis may be of more clinicalFalse-negative diagnosis may be of more clinical
Cytologic diagnosis of papillomas and well-differentiatedCytologic diagnosis of papillomas and well-differentiated
papillary transitional cell carcinoma (TCC) can be difficultpapillary transitional cell carcinoma (TCC) can be difficult
or impossible because the cells are nearly normal-or impossible because the cells are nearly normal-
Transitional cells are among
the most pleomorphic, benign
epithelial cells in the body,
ranging from little basal cells
somewhat larger than a
lymphocyte (approximately 10
µm) to huge multinucleated
superficial (umbrella) giant
cells (100 µm or larger).
The cells vary from triangular
to polyhedral to rounded, or
caudate to columnar.
parabasal-sized cells usually
predominate in voided
umbrella cells, groupsumbrella cells, groups
of cells, andof cells, and
aggregates are moreaggregates are more
commonly seen incommonly seen in
catheterized urine.catheterized urine.
Columnar transitional cells
are a normal and relatively
common finding in specimens
obtained by instrumentation of
They also can arise from the
urethra, particularly of men, as
well as in cystitis cystica.
Usually benign, but can also be
seen in well-differentiated
Reactive changes in
transitional cells caused by
radiation/chemotherapy, viral or
bacterial cystitis, drugs, or even
Features include high N/C ratio,
prominent nucleoli, darker and
coarser chromatin (still evenly
•Other cells: Renal tubular cells (associated
with kidney disease), Squamous cells
(common finding in urine), Prostatic cells
(normally found after prostatic massage),
Seminal vesicle cells (uncommon in urine,
but can be strikingly atypical in appearance
especially in older man), Endometriosis can
present in women with cyclic hematuria and
suprapubic pain, RBC’s, inflammatory cells,
giant cells, histiocytes, sperms and crystals.
(caused by(caused by
stones, trauma,stones, trauma,
etc); bizarreetc); bizarre
transitional cellstransitional cells
with darklywith darkly
coarse orcoarse or
Relative advantages and disadvantages of urine specimen types.
Benign LesionsBenign Lesions
Urolithiasis: IncreaseUrolithiasis: Increase
in cellularity even inin cellularity even in
voided urinevoided urine
specimens, includingspecimens, including
mechanical avulsionmechanical avulsion
of pseudopapillaryof pseudopapillary
groups of transitionalgroups of transitional
Significant cellularSignificant cellular
atypia, the nuclei mayatypia, the nuclei may
be enlarged andbe enlarged and
pleomorphic, irregularpleomorphic, irregular
in size and shape,in size and shape,
with an increased N/Cwith an increased N/C
ratio, hyperchromatic,ratio, hyperchromatic,
coarse chromatin.coarse chromatin.
•Cystitis: Cystitis is usually
caused by fecal flora, particularly
Escherichia coli, and also
faecalis, Staphylococcus, and
•The urine specimen contains
polymorphonuclear leukocytes, histiocytes,
red blood cells, and necrotic debris
•Atypical transitional cells, with irregular
outlines, enlarged hyperchromatic nuclei,
prominent nucleoli, and coarse chromatin
•Malignancy usually has more necrosis, but
usually less inflammation, than cystitis.
However, inflammation does not rule out
•Brunn’s nests (solid buds of transitional
cells), cystitis cystitica (small cysts lined
with transitional cells) and glandularis (cysts
lined with metaplastic glandular cells) are
normally a result of chronic inflammation
and may follow each other.
•Infections: Fungal infection can be isolated
finding or part of a systemic infection. Most
common types of fungi include Blastomyces,
Cryptococcus, Aspergillus, and Candida.
•Parasites include trichomonas, ameba and
•Herpes (multinucleation, molding,
margination with or without nuclear
•Cytomegalovirus (cytomegaly, basophilic
nuclear inclusion, thick nuclear membrane,
with or without intracytoplasmic or
intranuclear satellite inclusions).
•Human polyoma virus: DNA virus related
to HPV and JC virus family. The cells have
enlarged dark nuclei mimicking cancer,
particularly carcinoma in situ ("decoy cells")
and sometimes short, cytoplasmic tails
(known as "comet cells")
•The most characteristic feature is the
presence of a large, round, homogeneous,
opaque blue/black viral inclusion in the
•Malakoplakia: Granulomatous disease,
grossly, soft yellow plaques, about 3 to 4 cm
in diameter, occur in the bladder.
•Cytologically Giant cells, known as von
Hansemann histiocytes, abundant granular,
periodic acid-Schiff (PAS)-positive
•Radiation and Chemotherapy
•Cellular and nuclear
enlargement, N/C ratio is not
increased overall. Cytoplasmic
and nuclear vacuolizations are
common. Degenerative changes
are common as well.
Some histiocytesSome histiocytes
contain characteristiccontain characteristic
bodies. Round,bodies. Round,
laminated, usuallylaminated, usually
basophilic, butbasophilic, but
eosinophilic, calcifiedeosinophilic, calcified
inclusions about 5 toinclusions about 5 to
10 µm in diameter.10 µm in diameter.
•They occur three times as often in males, usually in patients over 50
years of age. Risk factors include aromatic amines, phenacetin,
cyclophosphamide, alkylating agents, schistosomiasis, smoking etc.
•WHO/ISUP classification system for urothelial neoplasm:
•Papillary urothelial neoplasm of LMP
•Low grade urothelial carcinoma
•High grade urothelial carcinoma
Extremely rare andExtremely rare and
occur almostoccur almost
exclusively in youngexclusively in young
patients. Thesepatients. These
cannot be recognizedcannot be recognized
cytologically unlesscytologically unless
an intact papillaryan intact papillary
frond is identifiedfrond is identified
•Papillary urothelial neoplasm of low
malignant potential and low grade
•The cytologic features of these two
lesions are similar.
•Cytologic Criteria: Cytoplasmic
homogeneity, high nuclear to
cytoplasmic ratio, irregular borders.
•Architectural criteria: Papillary
fragments with fibrovascular cores
(diagnostic but rare).
•Cell clusters without cores (not
specific: also seen with
•Irregular cell clusters (more
commonly associated with UC
than smooth cell clusters).
•Diagnosis of dysplasia is of
limited value in cytology, because
almost all patients have a
coexisting high grade lesion.
•High grade urothelial carcinoma:
•High nuclear to cytoplasmic ratio,
marked nuclear hyperchromasia, coarsely
granular chromatin, irregular nuclear
outline, large nucleoli (some cases).
•The background may contain necrotic
debris, blood, and inflammatory cells.
•The sensitivity of urine cytology for high
grade UC is 79% and specificity is
greater than 95%.
•Differential diagnosis includes, polyoma
virus, stones, normal upper tract
brushings/washings, treatment effect,
non-specific reactive changes.
•Other Malignant Lesions:
•Squamous cell carcinoma:
•Rare and strongly associated with
Schistosoma hematobium. A definite
diagnosis of squamous cell carcinoma
should be deferred to biopsy or
•Cytoplasmic keratinization, pearls,
bridges, angulated hyperchromatic
•The differential diagnosis includes
condyloma accuminatum of the bladder,
metastatic squamous cell carcinoma and
a squamous cell carcinoma of the
•Strongly associated with bladder
exstrophy and urachal remnants.
•Glandular differentiation is common in
otherwise typical urothelial carcinoma,
therefore the definitive diagnosis of pure
adenocarcinoma is left to biopsy.
•Clear cell carcinoma:
•Small clusters of obviously
malignant cells , abundant clear
cytoplasm, large irregular nuclei,
vesicular chromatin, large nucleoli.
•Small cell carcinoma:
•Very rare aggressive tumor
although the prognosis is better
than for those with SCC in other
Rare but canRare but can
potentially bepotentially be
diagnosed withdiagnosed with
urine cytology.urine cytology.
•Almost always occurs in patients
with poorly differentiated (gleason
score > or = 8)
•Prominent nucleoli and relatively
abundant cytoplasm. Clinical
history is very important in order
to avoid confusion with high grade
Renal cell carcinoma:Renal cell carcinoma:
Isolated cellsIsolated cells
moderate amountmoderate amount
of clear or granularof clear or granular
cytoplasm, round tocytoplasm, round to
irregular nuclei,irregular nuclei,
prominent nucleoli.prominent nucleoli.
•Diagnosing difficult or borderline
specimens: common patterns:
•It is advisable to use atypical as
sparingly as possible by classifying them
as either benign or suspicious.
•Common patterns that can be applied to
•Cell clusters in voided urine-
diagnose as negative
•Cytologic or architectural criteria
for a low grade lesion-diagnose as
•Rare small highly atypical cells-
diagnose as suspicious.
•Degenerated atypical cells
with intact nuclear outlines-
diagnose as suspicious.
•Rare mildly atypical cells-
try to diagnose as negative.
•DNA aneuploidy (FCA, image analysis)
•Bard bladder tumor antigen test (BTA).
•Nuclear matrix protein test (NMP 22
•Microsattellite instability assays.
•Hyaluronidase and hyaluronic acid
•Growth factors: acid fibroblast growth
factor, basic FGF, autocrine motility
factor, epidermal growth factor,
transforming growth factor-beta.
•Cell adhesion molecules, FISH etc.
•Most urines are negative.
•The value urine cytology for High grade
lesions in undisputed,
•Clusters of urothelial cells per se are of
limited use for the diagnosis of UC in
•The term dysplasia should be avoided.
•Upper tract lesions should be diagnosed
•Separating high risk from low risk
patterns may be of value in reducing the
number of atypical diagnoses.
•Still looking for a highly accurate
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