Non-Gynecologic Genitourinary Cytopathology
Moderator: Dr. Warick Delprado
Section 2 -
Urine Cytology – A Daily Approach
Douglass Hanly Moir Pathology
"Urine Cytology" has previously been referred to as difficult and poorly reproducible. Some of the
causes of this have been:
Some of the problems in the daily practice of urine cytology can be seen in the following case. A 70
year old female presented with haematuria. Investigation and subsequent bladder biopsy showed a
non-invasive low grade papillary urothelial carcinoma. Over the next nine months repeat cystoscopies
showed a PUNLMP and later a non-invasive papillary urothelial carcinoma with associated carcinoma in
situ. There was no invasion. She was treated with several courses of BCG. Twelve months after
presentation, biopsy showed chronic inflammation and atypical urothelium. At 15 months, urine cytology
(x3) was "malignant – high grade". Subsequent biopsy showed low grade papillary urothelial carcinoma.
Six months later, repeat cytology was "highly suspicious of malignancy". Single bladder biopsy showed
PUNLMP. Six months later, (two years after initial presentation) an enlarged para-aortic lymph node
biopsied showed metastatic high grade carcinoma, consistent with urothelial carcinoma. This case
demonstrates the major problems that can be encounted relating to classification, terminology and
communication. PUNLMP was considered by the clinician as an appropriate finding after "malignant" and
"highly suspicious of malignancy" cytology. The cytology was actually pointing to the initial high grade
carcinoma in situ which progressed to invasive malignancy. This confusion can lead to lack of faith in
urine cytology by clinicians and discomfort with performing urine cytology by cytologists and
- the confusion in classification and terminology, and a lack of
understanding of the pathobiology of urothelial neoplasms,
- perceived degenerative changes in cells caused by the so-called
toxic environment of urine resulting in reports along the lines of "atypical degenerate cells present"
which drive clinicians to distraction,
- the more glamorous areas of cytology, and associated disinterest in
urine, overshadowing the study and teaching of urine cytology, and
- urologists occasionally not finding any abnormality despite urine
cytology being specific and definite, resulting in a lack of confidence in reports, despite the fact that
that it is known that some carcinomas can take a long time to become clinical.
So how do cytopathologists and cytologists overcome these problems? This involves quality
maintainence and improvement. The best way is to:
- find out what you are doing, by reviewing practices and
- find out what you should be doing by reviewing diagnostic
criteria, and finally
- doing what needs to be done by setting in place an
approach that allows you to report accurately and reliably on a daily basis.
What are we doing?
It is important to understand or measure the reports being issued by a department. The purpose is to
ensure that all cytopathologists and cytologists are using the same terminology and criteria. A review
such as this can be done in two ways. Firstly, a series of cases can be reviewed and rescreened to
ensure no repeated errors are occurring. Ideally, this should be done with cases that have cytological
and pathological correlation. Secondly, a formal case review can be carried out with a fixed number of
known cases circulated to everyone within a department. Errors or differences in opinion should be
analysed and discussed.
What should we be doing?
Standard reporting terminology and guidelines should be agreed upon within a department. This should
start with ensuring that everyone is using the same terminology. Firstly, all reports should use the
current WHO (2004) classification of urothelial neoplasia. Secondly, criteria based upon published
series should be uniformly used in all reports.
What do we need to do?
A simple approach to urine cytology can be defined to take most of the heartache from
reporting urine. This involves attitudinal approach as well as an approach to each slide.
An Approach to Diagnosis in Urinary Cytology.
1. Don't panic
2. Be aware of the pecularities of urothelial neoplasia histopathology
This is covered in length in Dr Murphy's presentation. Based upon disagreement between pathologists,
and misconceptions of the pathology of urothelial neoplasia, urine cytology has been made, or at least
been made to seem, harder than it really is.
3. Remember basic cytology
Traditional criteria of malignancy still apply in urine cytology and allow recognition of nearly all
high grade lesions. Difficulties relate to low grade lesions, that are less clinically significant.
4. Apply standard terminology
Non gynaecological cytology is traditionally reported in four categories – negative, atypical,
suspicious and malignant. With some modification, these can be used in urine cytology. Use of the term
"atypical" is controversial and can be problematic. However, provided terminology is clearly defined and
explained to clinicians, the categories give good information and allow clear clinical recommendations.
The use of "dysplasia" is useful in the context of PUNLMP. Recommended reporting is:
- Negative (includes reactive)
- Atypical (not normal, but low likelihood of malignancy) –
can be reviewed and followed
- Suspicious (not normal, with high likelihood of
malignancy) - investigate
- Malignant – low grade or high grade carcinoma
- Dysplasia – "significantly abnormal cells present with
features short of malignancy and consistent with flat dysplasia or PUNLMP"
5. Look for patterns
Pattern recognition is an important aid in sharpening diagnostic accuracy. However, it is not the
diagnosis. Patterns draw attention to the possibility of malignant cells, which then must be
specifically identified. Diagnosis of malignancy eventually depends only on cellular criteria of
Traditionally, we have been taught, and have taught, that cellular tissue aggregates and papillary
fragments should be largely ignored when reporting urine cytology. They are often related to
instrumentation. Conventional wisdom was that one should note the presence of fragments, but look to
individual cells for a diagnosis. Whilst this is largely correct, the shape of cellular aggregates does
give additional information that assists in making a diagnosis. There are three important patterns:
- "Tissue fragments" - with curled, or balled shape.
These result from shed or displaced "intact" sheets of cells from a surface. They have rounded or
curled- up margins. There is often a surface along some of the margins. They usually occur as part of a
reactive pattern or as a result of instrumentation, particularly as part of a bladder wash. However,
they can occur in neoplasia, mainly transitional cell carcinoma in situ, and are more pronounced in
bladder washes. (C or J shape)
- "Papillary fragments" - branched, nodular crowding and
These result from being shed from the margins of papillary neoplasms. They are characterized by poor
surface definition and irregular, curled-up margins with nodular areas of overlapping cells. They are
seen in papillary neoplasia, both low and high grade. (E shape)
- "Cellular aggregates" - dissociating
These result from shedding of dissociating cells in loose clusters. These cells show loss of
cohesion and separation (falling apart), particularly at the edges. No surface is identified. This
pattern appears to be accentuated in bladder washes, and as such may be partly artefactual. It is seen
in high grade papillary neoplasia and transitional cell carcinoma in situ.
The presence of debris, inflammation or cellular material can alert to the possibility malignancy.
However, malignant cells must still be identified for a diagnosis.
- "Apoptotic Debris Cells"
Result from incipient necrosis of superficial urothelial cells in tumours. They are small nuclei
with hyperchromatic (dense) uniform chromatin, less than that of a leucocyte in diameter and with
variable cytoplasm. This pattern of cells is seen rarely in PUNLMP, but commonly in papillary tumours,
both low and high grade. It can also be seen in TCC in-situ. The pattern results from nuclear shrinkage
as part of cell loss from superficial layers. However, it may also be seen following intra-vesicle
therapy associated with extensive tumour necrosis. These cells should be recognized and used as a marker
for, but are not diagnostic of malignancy. A search should be made for classical malignant cells. If
these are absent, the appearances should be called suspicious rather than "atypical degenerate".
A difficult and time consuming presentation, characterised by an overwhelming acute inflammatory
cellular pattern that masks individual abnormal cells.
- "Squamous debris"
Numerous squamous cells can mask individual malignant cells
6. Know the clinical history
Whilst it is true that smears can be interpreted in isolation, patient history affects the
presentation on the slide. Is this an initial presentation or a recurrence? Has there been previous
therapy and what type? Is the specimen a urine or a bladder wash?
7. Look at the slide
Urine cytology should not be left till the end of the day after more important cytology has been
reported. Report as part of the routine work, taking your time and don't forget the high power lens to
search between the background.
Overall, there is a sequence of questions to the approach to urine cytology:
- New / Recurrence (? review previous) / Post treatment
- Urine / Bladder Wash / Catheter specimen / Ileal Conduit
- Normal / Inflammation / Diathesis / Apoptosis
- Bacterial overgrowth / Crystals / Sperm (caution)
- Tissue fragments
- Nil / number - ? urine / wash
- Curled / balled (?reactive) [J]
- Branched / papillary [E]
- Dissociating (insitu)
- Number / Populations (? <2 or >2)
- Apoptotic / Squamous (?metaplasia)
- Size (N/C ratio) / Position (central / eccentric)
- Shape - Uniform / irregular ?
- Smooth / Folds / Grooved / Sharp edges / angles
- Normal / Uniform / Granular / Irregular (? Quadrants)
- Size / Shape / Smooth / Angular
- N/C Ratio
- Vacuoles / solid / squamous
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