URINE CYTOLOGY

Richard Doughty
Avd for patologi
Ahus
The main purpose of urine cytology is

To detect High Grade Urothelial Carcinoma

Outline
¨ Urine – the basics
¨ A little on the history of claasification systems.
¨ What is the goal of urine cytology?
¨ Why to standardize, why Paris?
¨ What is the guiding principle?
¨ What are diagnostic categories?
¨ What are the criteria?
¨ What adjuvant studies?
¨ What are future clinical and research needs?
Bladder cancer current status

¨ ~ 76,900 new cases in 2016 in the USA

¨ ~ 16,390 deaths due to bladder cancer
¨ 4th most common ca in men and 9th in women (1 in 44 people)
¨ 9th most common cause of cancer death (F>M)
¨ ~ 75% non muscle invasive bladder cancers (superficial bladder
¨ cancers), Ta, Tis, T1
¨ ~ 30% 70% recurrence
¨ ~ 5% 15% progression (<1% LG Ta)
¨ > 535,000 people in the US are survivors of this cancer

¨ Highest per patient cost from dx to death of all cancers

¨ $4.1 billion/year spent to tx bladder cancer

Nielsen ME et al. Trends in stage specific incidence rates for urothelial carcinoma of the bladder in the United States:
1998 to 2006. Cancer 2014:120:86
In Norway....
¨ 2015: 1731 new cases of cancer in the urinary
bladder, ureters or urethra
¤ 1262 men
¤ 469 women
 The urinary tract – the basics

Upper urinary tract

Lower urinary tract

What is urine?
Urine – a definition
¨ Urine is a liquid by-product of the
metabolism in humans and in many
animals. Urine flows from the
kidneys through the ureters to the
urinary bladder.
Urine composition

Not the perfect cell

presevation medium!!
Clinical Indications of Urine Cytology

q Hematuria
q Follow-up of patients treated for Urothelial
Carcinoma (UC)
q High-risk of bladder cancer
What can you expect to find in a
normal urine?
Normal Urinary Elements
q Urothelial cells
q Intermediate and superficial (umbrella) cells (voided urine)
q Intermediate, superficial and basal cells (catheterized urine,
washing)
q Squamous cells
q Miscellaneous findings
q Prostate and seminal vesicle epithelial cells
q Renal tubular cells and casts
q Corpora amylacea
q Crystals
q Inflammatory cells
q Degenerated intestinal epithelial cells (ileal conduit)
Umbrella cells
• Low N/C ratio
• Pale finely granular chromatin
• Smooth nuclear shapes
• Multinucleation common
• Cytoplasm transparent
 Intermediate and basal cells

• High N/C ratio

• Chromatin darker than
superficial cells
• Nuclei smaller than
superficial cells
• Nuclear shape round
• Even nuclear spacing
Normal Urinary Elements

Melamed-Wolinska Bodies
Casts
q Renal Diseases:
q RBC casts: Glomerular diseases
q WBC casts: Tubulointerstitial diseases and transplant
rejection
q Renal tubular casts: Renal parenchymal diseases

q Fatty casts: Nephrotic syndrome

q Physiologic:
q Hyaline and granular casts: Secondary to dehydration,
fever, exercise etc
Normal Urinary Elements
RBC Cast Renal Tubular Cast

Rbc cast

Rbc cast

Corpora Amylacea

Rbc cast
Non-Urinary Elements

Seminal Vesicle Cells Endometrial Cells

Infections -Fungal
Crystals
q Common finding, no clinical significance in most cases
q Crystals analysis part of routine urinalysis rather than urine
cytology
q Uric acid: most common, variable shape
q Triple-phosphate: prism shaped and resemble coffin lids
q Ammonium biurate: “Thorn apples”
q Calcium Oxalate: Oval, dumbbell shaped
q Pathologic crystals: much less common, bilirubin (brown
granules and needles), cholesterol , cysteine (hexagonal
plates), leucine (spheres with radiating striations) and tyrosine
(slender needles)
Types of Urinary Specimens
q Voided Urine
q Catheterized Urine
q Bladder Washings
q Upper Tract Washings and Brushings
q Ileal Conduit Samples

Urine samples is a relatively easy sample to

obtain….maybe
Physicians have it easy....

+ + =
+ =
+ =
Voided Urine
q Collected 3-4hrs after the last void (100-300ml)
q Sparse cellularity, superficial and intermediate cells
q Degenerative changes
q Squamous cells common
q Trigone or genital tract contamination in women
q Inflammation or irritation

q Non-cellular constituents such as crystals, casts,

corpora amylacea
q Non-invasive technique and no instrumentation effect
Catheterized Urine
q Moderate to highly cellular
q Superficial, intermediate and basal cells
q Poor preservation with pronounced degenerative
changes in pooled specimens
q Urethra not sampled
q Instrumentation artifacts: Urothelial clusters can mimic
low-grade urothelial carcinoma
q Risk of infection
Catheterized Urine

Basal Urothelial Cells in Catheterized Urine Specimen

Bladder Washings

q Obtained through a catheter by irrigating the

bladder with 5-10 pulses of 50 ml sterile saline
q Better cellularity and preservation
q Less contamination by background debris
q Increase sensitivity (66%-77%)
q Only bladder epithelium represented – upper tract
not sampled
q Quality of sample dependent on the skill of urologist
Bladder Washings
Upper Tract Washings / Brushings
q Comparable sensitivity to other type of urinary
specimens
q Technically and morphologically challenging
q Prone to false positive results – marked cellularity
q Comparison of bilateral specimens (normal vs
lesional) helpful in making diagnosis
q Cytological diagnosis with conservative approach
q Ureterectomy or nephrectomy
Urethral Brushings
Urethral Brushings
Ileal Conduit
q Surveillance of ureters and
renal pelves post cystectomy
q Cellular specimen with large
amount of degenerated
intestinal epithelial cells and
background debris
q Malignant cells may be
obscured
Take home from sampling:

• There is a balance between the

invasiveness of the sampling method and
the cellularity obtained
The history of systems for reporting
urine samples
Urine comtemplation
¨ Avicenna, physician and philosopher (980 – 1037),
advocated systematic analysis of urine:
¤ Colour

¤ Density
¤ Sendiment – calculus, abscess or tumor
¤ Odor – tumor
The age of uroscopy...
¨ Historic medical practice of visually examining a
patient's urine for pus, blood, or other symptoms of
disease
From urine analysis to urine cytology

¨ Rise of modern light microscopes – 1600s

¨ No mention of cellular elements in urine until 1800s

Alfred Donne 1801 - 1878 Hermann Lebert 1813 - 1878

Modern times.....

1928 1940s - onwards Dorothy Rosenthal

Georgios Papanikolaou Leopold Koss The Johns Hopkins
Pap smear `Father of urine Hospital template
cytology’ for urologic cytology samples
Onwards to Paris!
18th International Congress of Cytology, Paris,
May, 2013
• “Paris Group” – all participants of two Urine
Cytology Symposia
• Outline of the Paris System for Reporting
Urinary Cytopathology
• Ultimate goal – detection of HGUC
• Sponsorship by the ASC and IAC
• Contract with Springer
• Numerous face to face meetings
The move to standardise...

2001 2007
The Paris System for Reporting Urinary
Cytology
Why to standardize reporting of
urinary cytology?

¨ Reproducibility
¨ Improvement of communication
¨ Atypical cells
¤ Wide intraobserver variability
¨ Nationally rates of atypical vary among institution
¤ Range from 2% to 30% (51% atypical + suspicious)
For example
Irregulære, degenererte urotelceller av usikker
betydning.....
The Paris System
1. Pathogenesis of Urothelial Carcinoma
2. Adequacy
3. Negative for High Grade Urothelial Carcinoma
4. Atypical Urothelial Cells
5. Suspicious for High Grade Urothelial Carcinoma
6. High Grade Urothelial Carcinoma
7. Low Grade Urothelial Neoplasm
8. Other malignancies, both primary and secondary
9. Ancillary Studies
10. Clinical management
11. Preparatory techniques relative to Urinary Tract samples
System has to be build based on:
¨ Consensus
¨ Evidence
¨ Inclusion
¨ Acceptance
¨ Understanding
A little on grading and staging
¨ Grading
¤ Histological appearance
n Low grade
n High grade

¨ Staging
¤ Non muscle invasive bladder cancer (NMIBC)
n Tis, Ta, T1
¤ Muscle invasive bladder cancer (MIBC)
n >T1
TNM classification for bladder cancer

Tis
 Pathogenesis of Urothelial
Carcinoma
Eva M. Wojcik and Stefan E. Pambuccian

Papillary Pathway Normal Urothelium Non-Papillary Pathway

80% 20%
9p-, 9q-
p16

Hyperplasia Dysplasia
Genetically Stable Genetically Unstable
FGFR3 (~85%) p53 (~60%) <10%

RAS (?)

Low Grade Carcinoma High Grade Carcinoma Carcinoma in situ

Recurrence Recurrence

Invasive Carcinoma
Bladder cancer – more than one disease?

• ~ 75 % Non Muscle Invasive (Ta/T1)

• Good prognosis
• Recurrence
• 10% 15% progression (LG Ta <1%)*

• ~ 25 % Muscle Invasive (> T2)

• >60% overall survival
“Approximately 80% (of Ta bladder tumors) appear to follow a benign course without
developing invasive tumors or dying of bladder cancer”
Question…. “Carcinoma”?

GU GI
Question…. “Carcinoma”?

CARCINOMA

ADENOMA
 Hansen
Mr. Smith - You have a bladder cancer
What really matters?

High Grade Urothelial Carcinoma

 Diagnostic Categories

Reality

Hope
Positive Atypical/Suspicious Negative

HGUC Everything else

Classifications
WHO 1973

Papilloma Grade I Grade II Grade III

Papilloma PUNLMP Low Grade High Grade

WHO/ISUP 2004

~ 10-20% ~ 50-60% ~ 80-90%

URINE CYTOLOGY SENSITIVITY

Very high probability that we are going to be wrong

Evolution of the Classification

?LG
?
HG

Owens et al. Cancer Cytopathology 2013

NEW paradigm
• It is all about High Grade Urothelial Carcinoma
• Negative for High Grade Urothelial Carcinoma

AUC SHGUC HGU

Quality and Quantity Quantity
C

• LGUN – Low Grade Urothelial Neoplasm

But first adequacy
¨ Surprisingly little data...

¤ Prather J, Arville B, Chatt G, et al. Evidence based

adequacy criteria for urinary bladder barbotage
cytology. Journal of the American Society of
Cytopathology.4: 57 62.
¤ VandenBussche CJ, Rosenthal DL, Olson MT. Adequacy in
voided urine cytology specimens: The role of volume and a
repeat void upon predictive values for high grade urothelial
carcinoma. Cancer Cytopathol. 2015.
Prather J, Arville B, Chatt G, et al.
Table 1. Prospective study.

Cellularity Sensitivities

AUC+ HGUC

<10 per 10 hpfs 60.5 37.2

≥10 per 10 hpfs 95.2 76.2

P value 0.0001 0.0004

<20 per 10 hpfs 68.3 43.3

≥20 per 10 hpfs 100.0 88.0

P value 0.001 0.0001

Volume is important…
Adequacy of Urine Specimens (Adequacy)
Lets take a break!
Diagnostic categories

1. Negative for High Grade Urothelial

Carcinoma
2. Atypical Urothelial Cells
3. Suspicious for High Grade
Urothelial Carcinoma
4. High Grade Urothelial Carcinoma
5. Low Grade Urothelial Neoplasm
6. Other malignancies, both primary
and secondary
Negative for High Grade Urothelial Carcinoma
(Negative)

Definition of Negative for High Grade Urothelial

Carcinoma
• A sample of urine, either voided or instrumented, may
be considered benign, i.e., NHGUC, if any of the
following components are present in the specimen:
– Benign urothelial, glandular, and squamous cells
– Benign urothelial tissue fragments (BUTF) and
urothelial sheets or clusters
– Changes associated with lithiasis
– Viral cytopathic effect; polyoma virus (BK virus—
decoy cells)
– Post therapy effect, including epithelial cells from
urinary diversions
Benign Superficial (Umbrella) Urothelial Cells
“Atypical” Umbrella Cells
Glandular Cells

• Sources: endometrium, prostate, kidneys, urachal remnants,

metaplasia
Cystitis cystica/glandularis
Renal Tubular Epithelial Cells
 Benign Urothelial Tissue Fragments BUTF

Onur, I., Rosenthal, D. L., & VandenBussche, C. J. (2015). Benign appearing urothelial tissue fragments in noninstrumented
voided urine specimens are associated with low rates of urothelial neoplasia. Cancer cytopathology, 123(3), 180-185.
Nephrolithiasis – 3D fragments
Stone Atypia
Systemic Chemotherapy Changes
q Degenerative changes with
frayed cell borders
q Enlarged hyperchromatic but
smudgy nuclei
q Vacuolated cytoplasm
q Irregular dark nucleoli
q Multinucleation
Chemotherapy Changes

Thiotepa

Mitomycin High-grade UC
Intravesical Chemotherapy Changes
q Predominantly effect the superficial
cells
q Marked cytomegaly with abundant
vacuolated cytoplasm and one or
more nuclei
q Nuclear chromatin chunky, clumped,
deeply staining or structureless and
smudgy with smooth borders
q Prominent nucleoli
q Frayed borders
q No significant effect on neoplastic
cells
Immunotherapy
Radiation Changes
¨ Cytomegaly with binucleation or
multinucleation
¨ Enlarged nuclei without significant
increase in N/C ratio
¨ Smudgy chromatin
¨ Nucleoli
¨ Cytoplasmic polychromasia and
vacuolation
Malakoplakia
Von Kossa Stain

Malakoplakia with Michealis Gutmann Bodies

Malakoplakia: Histiocytes with abundant granular cytoplasm filled with
bacteria and bacterial fragments
Seminal Vesicle Cells
Bladder Diversion Urine

Melamed – Wolinskabody
Infections -Viral
q Polyomavirus
q Infectsboth healthy and immunocompromised individuals
q 4% of urine specimens

q No clinical significance in immunocompetent

q Herpes: Uncommon, immunocompromised patients

q CMV: Most commonly effects renal tubular cells
q HPV: Vaginal contamination
Infections - Viral

CMV HSV HPV

Infections - Viral

Polyomavirus Cytopathic Changes

Things are never that easy......
88-year-old man with a history of T1 HGUC previously treated
by local excision. F/U bx negative. Cystoscopy – negative.
• Polyoma → Negative for High GradeUrothelial
Carcinoma

How about
these?
What is Atypia

Positive Suspicious Atypical Negative

What do YOU call atypia in urine specimens?
1. There are rare cells, reminiscent to
that of high grade UC
2.Negative for worrisome
Lots of cs, High Gradefor
Urothelial Carcinoma
low grade
UC
3. Other (degenerated cells, cells/
groups that don’t fit in either
group above)
Diagnostic categories
What is atypia? Findings in literature

1. High nuclear cytoplasmic ra5o (>0.7)

2. Nuclear hyperchromasia
3. Coarse, clumped chroma5n
4. Irregular nuclear membranes

Atypia Suspicious Positive

Atypical Urothelial Cells (AUC)

Criteria for AUC

• Non superficial and non degenerated urothelial cells
with an
high N/C ratio > 0.5 (required)
and one of the following:
• Hyperchromasia (compared to the umbrella cells
or the intermediate squamous cell nucleus)
• Irregular clumpy chromatin
• Irregular nuclear contours
Degeneratio
n
N:C ratio of 0.5???
 Suspicious for High Grade Urothelial
Carcinoma (Suspicious)
Criteria for SHGUC
• Non superficial and non degenerated urothelial cells with an
high N/C ratio > 0.7 (required)
• Hyperchromasia (compared to the umbrella cells or the
intermediate squamous cell nucleus) (required)

and one of the following:

• Irregular clumpy chromatin
• Irregular nuclear membranes

<10 cells
 Suspicious for HGUC vs. Positive HGUC
Quantity matters..
“The number of atypical urothelial cells is an important criterion to
classify urine cytology specimens into the ‘positive’ or the
‘suspicious’ categories. A cut off number of
>10 cells to render a definitive diagnosis of HGUCA seems
valid from the clinical standpoint .”

JASC 2015;4(4)232–238

5 – 10 cells – gray zone, based on experience, history,

individual threshold, etc
Not only quantity and quality matter...
High Grade Urothelial Carcinoma (HGUC)
• Cellularity: At least 5–10 abnormal cells
• N/C ratio: 0.7 or greater
• Nucleus: Moderate to severe hyperchromasia
• Nuclear membrane: Markedly irregular
• Chromatin: Coarse/clumped
High-grade UC

Bladder Washing Squamous differentiation

Other Notable Cytomorphologic Features

• Cellular pleomorphism
• Marked variation in cellular size and shapes, i.e.,
oval, rounded, elongated, or plasmacytoid
(Comet cells)
• Scant, pale, or dense cytoplasm
• Prominent nucleoli
• Mitoses
• Necrotic debris
• Inflammation
High-grade UC - Differential Diagnosis

q Polyomavirus
q Stone atypia
q Normal upper tract washing or brushings
q Treatment effect
q Non specific reactive changes
Squamous differentiation Glandular differentiation
What happened to Low grade urothelial
neoplasia (LGUN)??

• Almost impossible to diagnose without a mini

biopsy with fibrovascular core
• Cytologically normal nuclei
• Is it truly a carcinoma?
• More common than HGUC
• BUT, not life threatening
Low Grade Urothelial Neoplasia (LGUN)
• LGUN combined cytologic term for low grade
papillary urothelial neoplasms (LGPUN) (which
include urothelial papilloma, PUNLMP and LGPUC)
and flat, low grade intraurothelial neoplasia

LGU LGUN
C
Cytologic Criteria of Low Grade Urothelial
Neoplasia (LGUN) (regardless of the specimen
type: voided or instrumented):
• Three dimensional cellular papillary clusters (defined
as clusters of cells with nuclear overlapping, forming
"papillae") with fibrovascular cores with capillaries
Cytologic Criteria of Low Grade Urothelial
Neoplasia (LGUN) (regardless of the specimen
type: voided or instrumented)

Cell Block
How about these????

Negative for HGUC

Suggestive of LGUN
G. Barkan, MD
 Nuclear:Cytoplasm Ratios

AUC

SHGUC
+
HGUC

Zhang ML, Guo AX, VandenBussche CJ. Morphologists overestimate the nuclear-to-cytoplasmic
ratio. Cancer Cytopathol2016;124:669–677.
What does the urologist do the
cytology report?????
Clinical Management

• From the standpoint of the urologist, the

workup for AUC should be individualized
based on the risk assessment of the patient

• From a practical standpoint, the clinical

management of “suspicious for HGUC” is
similar to a “positive for HGUC” diagnosis

• Transurethral resection establishes the

histologic diagnosis and is therapeutic for
most solitary low grade tumors
Clinical Management
Category Risk of Management
Malignancy
Unsatisfactory/Nondiagnostic ? (<5%) Repeat cytology, cystoscopy in 3
months if increased clinical suspicion
Negative for HGUC 0-2% Clinical follow up as needed

Atypical Urothelial Cells (AUC) 8-35% Clinical follow up as needed. Use of

ancillary testing.
Suspicious for HGUC 50-90% More aggressive follow up,
cystoscopy, biopsy
LGUN ~10% Need biopsy to further evaluate
grade and stage
High Grade UC >90% More aggressive follow up,
cystoscopy, biopsy, staging
Other malignancy >90% More aggressive follow up,
cystoscopy, biopsy, staging
 Rate of Atypia at Loyola per pathologist
35,00 %

30,00 %

25,00 %

20,00 %

15,00 %

10,00 %

5,00 %

0,00 %
2008 2009 2010 2011 2012 2013 2014 2015 2016
Diagnostic categories

1. Negative for High Grade Urothelial

Carcinoma
2. Atypical Urothelial Cells
3. Suspicious for High Grade
Urothelial Carcinoma
4. High Grade Urothelial Carcinoma
5. Low Grade Urothelial Neoplasm
6. Other malignancies, both primary
and secondary
Other Malignancies Primary and Metastatic and
Miscellaneous Lesions
 ADC Clear cell adc bladder

Lymphoma Melanoma
Squamous Cell Carcinoma
q 5% of bladder cancers
q Pure squamous cell carcinoma rare
– associated with caliculi,
diverticuli, schistosomiasis
q Squamous differentiation in UC
q Cytoplasmic keratinization
q Hyperchromatic angulated nuclei
Primary Adenocarcinoma
q Rare, <2% of bladder
cancer
q Colonic type, most common
q Signet ring type
q Clear cell adenocarcinoma
Clear cell adenocarcinoma
Secondary Tumors
q Prostatic Adenocarcinoma
q Seen in high-grade prostatic
carcinoma
q Large cohesive three
dimensional clusters with ill-
defined cell borders
q Prominent nucleoli with
relatively abundant cytoplasm
q Dark nuclei resembling UC

q History helpful !
Secondary Tumors

Colonic Adenocarcinoma Endometrial

Adenocarcinoma
ANCILLARY TECHNIQUES
Nuclear / cytologic atypia NFHG AUC/SHGUC HGUC
8%-30%

low moderate/high certain

Probability of high grade UC
Ancillary Urine Based Techniques
q DNA ploidy
q Bladder Tumor Antigen (Bard BTA stat®)
q Nuclear Matrix Proteins (NMP22™)
q UroVysion™
q ImmunoCyt/uCyt™
q Telomerase
q Hyaluronic Acid Hyaluronidase
q Fibrin-Fibrinogen Degradation Product
UroVysion
q Chromosomal abnormalities in UC first described in
1990s
q Initial studies tested single chromosome probes
q Suklova et al published first study with multiple probes
(10 probes tested)
q Highest sensitivity achieved with combination of 4 probes
q Chromosome 3 (CEP)
q Chromosome 7 (CEP)
q Chromosome 17 (CEP)
q Chromosome 9p21 (LSI probe)
q Sensitivity: 84% Specificity: 92%
q Cutoff: 5 abnormal cells
Ancillary Studies in Urinary Cytology
UroVysion
q Multicolor multitarget FISH UroVysion test approved by
FDA in 2001
q Approved Indications:
q Surveillance of patients with bladder cancer
q Detection of bladder cancer in persons with hematuria
suspected of having bladder cancer
q Meta-analysis of several studies by Hajdinijak
q Sensitivity (72%) ; Specificity (83%)
q Targeted-UroVysion (CK7 immunophenotyping followed
by UroVysion) improves diagnostic efficiency
Summary

q Most urine specimens are negative

q Diagnosis of low-grade UC remains challenging due to
overlapping features with reactive atypia
q Urine cytology has high accuracy for high-grade lesions
q FISH (UroVysion) more sensitive than cytology in detection of
UC but produces more false positive results. Data suggest its
use as a reflex test following equivocal cytologic diagnosis
q Upper tract urinary samples including FISH should be
interpreted with reserve due to higher false positive rate
FISH vs. Cytology
¨ FISH more sensitive but less specific than urine
cytology
¨ PPV of urine cytology in HGUC > 90%
¤ PPV of FISH: as low as 50%
¤ Cytology= 7-10 times cheaper (Murphy 2009)
¤ Combined FISH & Cytology
n 98% sensitivity and > 95% specificity
¨ FISH-neg patients (low risk) may be allowed
extended time intervals between cystoscopies
 Final take home message

¨ HGUC – this is the one that matters –

Negative for HGUC
¨ The diagnosis “atypia” should not be used as
a waste basket and dx should be based on
criteria Atypia
¨ LGUN – new diagnostic category, based on
presence of fibrovascular cores TPS
¨ Not all malignant cells in urines are urothelial
carcinoma
¨ Future studies are needed for validation of
TPS
Thank you for listening!

Any questions?
References
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