URINARY CYTOLOGY: LOW-GRADE UROTHELIAL

NEOPLASM AND HIGH-GRADE UROTHELIAL

LESION. CYTOHISTOLOGIC CORRELATION

Daniela Gil Oliveira

Coimbra, 19 of January of 2023
 Daniela Gil Oliveira

Urinary cytology: Low-grade

Urothelial Neoplasm and High-grade
Urothelial Lesion. Cytohistologic correlation

Tutor: Cristina Paula Gonçalves dos Santos Agapito

Tutor: Vítor Manuel Leitão de Sousa

Coimbra, 2023
Table of Contents

1 - Summary ................................................................................................................. 1

2 – Technical description ............................................................................................... 2

2.1 – Literature revision ................................................................................................................. 2

2.2 – Aim......................................................................................................................................... 4

2.3 - Research Plan and Methods................................................................................................... 4

2.4 – Tasks ...................................................................................................................................... 7

2.5 – Ethical Comission ................................................................................................................... 8

2.6 – Project Management and Planning ....................................................................................... 9

3 – Research Team ...................................................................................................... 10

4 – Bibliographic references ........................................................................................ 12

I
 1 - Summary
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Bladder cancer is the 10th most prevalent cancer worldwide, being most common in men and
elderly people. It is related to tobacco consumption and the most common symptom is
hematuria.

Urothelial carcinomas represent the majority of bladder cancers and can be divided into two
distinct pathways: hyperplasia and dysplasia, leading to low-grade and high-grade lesions,
respectively.

Urinary tract cytology (UTC) is an essential noninvasive test for the diagnosis and follow-up of
urinary tract cancers and for surveillance of their recurrences and demonstrates high specificity
and sensitivity in detecting high-grade urothelial carcinomas (HGUC), as opposed to low-grade
urothelial neoplasms (LGUN) detection. For this reason, the updated edition of the Paris System
for Reporting Urinary Cytology (TPS) incorporated LGUN diagnosis into the negative for HGUC
(NHGUC) category in order to provide a more practical and useful diagnostic category.

The low sensitivity and specificity of urinary cytology in identifying the different grades and levels
of invasion of urothelial carcinomas is a challenge for cytopathologists. Therefore, it is crucial to
correlate the cytologic findings with the histological features of the correspondent biopsies, since
the histologic diagnosis is considered the gold standard method for diagnosing urothelial
carcinomas and an important predictor of the prognosis.

The aim for this study is to compare cytological bladder washing samples previously classified as
LGUN and HGUC with the correspondent histological samples in order to correlate the benign and
malign diagnoses given by both analyses.

Key words: Carcinoma; Bladder washing; Neoplasm; The Paris System; Cytology; Histology;
Diagnosis

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2 – Technical description

2.1 – Literature revision

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According to the World Health Organization (WHO), bladder cancer is the 10th most prevalent
cancer worldwide, being the 6th most common in men (1,2). It is strongly related to tobacco
consumption as well as advanced age and the most common clinical manifestation is painless
hematuria (3,4). Most bladder cancers are classified as urothelial carcinomas, which are divided
into two pathogenic pathways: hyperplasia, the more frequent pathway leading to low-grade
lesions, and dysplasia, which is less common and progresses to high-grade tumors (5).

Urinary tract cytology (UTC) is an essential noninvasive test for the diagnosis and follow-up of
urinary tract carcinomas and for surveillance of their recurrence (3,5,6).

The Paris System for Reporting Urinary Cytology (TPS) is a recently developed standardized
reporting terminology system that focuses on the identification of high-grade urothelial
carcinomas (HGUC), since it demonstrates high sensitivity and specificity for its detection. UTC has
been reported to have low sensitivity and specificity in identifying and grading low-grade
urothelial neoplasms (LGUN) (5–9), as LGUN’s features often overlap with negative and reactive
or inflammatory cases due to cellular cohesiveness and the lack of nuclear dysplasia detected in
the urine specimens (7–9). In addition, UTC is unable to morphologically distinguish neither
invasive and noninvasive features nor other key criteria to LGUN’s grading (6,10). While in the
first edition of The Paris System LGUN was a separate category, in the updated edition it was
decided to eliminate the chapter regarding LGUN and incorporate its criteria into the negative for
high-grade urothelial carcinoma (NGHUC) category. The purpose of incorporating LGUN on
NHGUC category was to state the absence of HGUC and to provide a more practical and useful
diagnostic category, since the necessary criteria for LGUN described in the first edition was the
presence of fibrovascular cores, which has been reported rather infrequently. However, the
concept is not entirely gone, since there are specific cytologic features that describe low-grade
lesions. For this reason, the diagnostic reports must include a comment or a secondary diagnostic
with the LGUN’s features described (11,12).

Cytologic criteria for HGUC are internationally accepted and have been successfully implemented,
providing an accurate and reliable diagnosis. It has been described as samples containing a
minimum of 5 to 10 abnormal cells with high nuclear to cytoplasm (N/C) ratios (equal to or higher
than 0,7), moderate to severe nuclear hyperchromasia (with rare exceptions of hypochromasia),
coarse and clumpy chromatin, marked nuclear membrane irregularity, prominent nucleoli,
increased pleomorphism and frequent mitotic activity. These features are easy and accessible to
visualize and identify by urinary cytology, which may explain its high specificity and sensitivity in
detecting HGUC.

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As for LGUN, it is common to observe cells presenting bland cytomorphology, such as slightly and
uniformly increased N/C ratios, mild hyperchromasia, cytoplasmatic homogeneity, often nuclear
membrane irregularity, which may lead to a misinterpretation as a benign or an atypical specimen
due to the overlap in their morphologic characteristics. For that matter, an accurate diagnosis of
LGUN has specific and strictly defined criteria and should include only specimens with innocuous
cells and fibrovascular cores. The cells are usually arranged in cell clusters and exhibit papillary
architecture (5–9,12–14).

The interobserver variability is a significant issue in the cytologic diagnosis of LGUN. Wojcik et al
evaluated the accuracy of the cytologic diagnosis of LGUN and the interobserver agreement
through key cytologic criteria for LGUN previously described in the literature. Even with a specific
reporting category for LGUN diagnosis, it was reported a poor agreement among the
cytopathologists’ reviews, regardless of their experience in the area (15). Since urinary tract
cytology shows low sensitivity and specificity in LGUN diagnosis and a limitation to differentiate
the several grades of urothelial papillary neoplasms, the correlation with the bladder washing
specimen’s corresponding biopsy and/or biopsy follow up is crucial. Urinary tract cytology (UTC),
besides being a noninvasive technique for screening and diagnosing urothelial carcinomas,
represents a larger surface area of the urinary tract as compared to the histologic diagnosis, which
besides only sampling a limited area, is the standard method for diagnosing urothelial carcinomas
and determining follow-up and further patients’ management (5,7,10,15–19).

The low sensitivity and specificity of urinary cytology in identifying the different grades and levels
of invasion of urothelial carcinomas is a challenge for cytopathologists, since it impacts on the
diagnosis of these tumors (5–7,9). Due to this fact, the correlation with the histological findings of
the corresponding biopsies is crucial, as they allow the distinction of the different
histopathological features that define the tumor as benign or malign, the low- or high-grade of
the tumor and the detection of invasion or its absence (3,20,21).

The histological stratification of urothelial carcinomas into different categories such as invasive or
non-invasive and low- or high-grade is aimed for subdividing the tumors into prognostic groups so
that different treatments can be properly administered based on the grade and muscle invasion
of the tumor (21).

The statistical analysis of the correlation between the results of cytological and histological
diagnosis, the latter being considered the gold standard for the diagnosis of urothelial
pathologies, will enable the evaluation of the sensitivity and specificity of urinary cytology to
detect benign or malignant lesion by analyzing the concordance between the results of both
diagnostic methods. This investigation will assess whether results diagnosed as LGUN on cytology
are actually negative for malignancy (given that LGUN has been incorporated from the NHGUC
category) and further whether those diagnosed cytologically as HGUC show malignancy
histologically.

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2.2 – Aim
(max. 600 characters without space) 598
The aim of this study is to compare cytological bladder washing samples previously classified as
low-grade urothelial neoplasms (LGUN) and high-grade urothelial lesions (HGUC) with histological
samples from corresponding biopsies in order to verify whether samples classified as LGUN
correspond to benign or malignant samples and whether those classified as HGUC represent
malignancy. This cytohistological correlation will allow assessing the sensitivity and specificity of
the new Paris Classification to detect benignity or malignancy, as well as grading the lesions and
thus predicting the biological behavior of the disease, a crucial step in determining patients'
follow-up and treatment.

2.3 - Research Plan and Methods

(max. 10000 characters without space) 7308
This project consists of an observational, analytical, cross-sectional study on the correlation
between cytological and histological findings of LGUN and HGUC in patients aged over 35 years
old, whose bladder washings and biopsy samples as well as statistical data were processed at the
Anatomopathological Diagnostic Center (CEDAP).

In this study, there will be no direct intervention of the researcher in the laboratory processing,
but a data gathering from the samples processed at CEDAP.

All the information gathered will be described in English and in Portuguese and all the literature
used in the bibliographic search is available in the PubMed/MEDLINE database, all of which was
published between 2015 to the current date.

In order to provide greater accessibility to articles of interest to this study, some MeSH terms
were defined, such as: “Paris System for Reporting Urinary Cytology”, “Urothelial Carcinoma”,
“Neoplasm”, “Correlation” “Cytology”, “Histology”.

The research plan for this study requires a sequence of tasks to be executed that will culminate in
the writing of the final scientific paper.

Task 1: Scientific information research

Description: First, the research on the topic of this project had to be conducted, in order to be
able to make decisions regarding the tasks to be performed and which methods and materials to
employ, as well as to deepen the knowledge on the topic. For that purpose, the
PubMed/MEDLINE database was consulted and essential information of interest for this project
was collected, such as the key criteria for each of the above-mentioned diagnoses, cytological and

4
histological characteristics of both, and articles about the correlation of both. All the information
gathered is available in the referred database, and all the literature mentioned was published
between 2015 and the current date.

Task 2: Selection and characterization of the sample for the research study

Description: In order to obtain a significant sample, a minimum of 60 individuals over the age of
35 years with previous clinical information or suspicion of bladder disease from January 2022 to
May 2023 will be selected. The samples of interest for the study are samples of LGUN and HGUC,
which are more prevalent in people of advanced age (hence the exclusion of samples from
patients under 35 years of age).

Task 3: Submitting the project to the Ethics Committee of the Polytechnic Institute of Coimbra

Description: Before proceeding with the following tasks required for the study, it is necessary to
submit the project and its objectives to the Ethics Committee of the Polytechnic Institute of
Coimbra (CEIPC). The samples to be used in this study are external to CEDAP, so obtaining
informed consent to be provided to the individuals will not be the objective of the submission of
the project to CEIPC, but their approval for the collection of clinical and statistical data of the
patients whose samples will be used to conduct this study. In the request for authorization for the
study, it has been stated that there are no associated risks or any costs or compensation for
participating in this study and further that there is no financial interest motivating it. The
information collected will be for the exclusive use of the study and confidentiality and anonymity
will be guaranteed, since the identification will be made through a code and will not be
referenced in any sample. After the analysis of the information collected, all data will be stored in
an encrypted database and protected by password.

Task 4: Collection of clinicopathological and statistical data given from CEDAP in a population of
patients

Description: Upon approval of the project by the CEIPC, the collection of clinicopathological and
statistical data from the patients could proceed. For this study, as previously mentioned, a
minimum of 60 individuals aged over 35 years old with suspected or previous clinical information
of bladder disease will be considered. As relevant information, the following data will be
gathered: gender, age, and clinical history.

Task 5: Laboratory processing of cytological and histological samples

Description: In terms of sampling, the samples used in this study are external to the institution,
meaning that the samples are collected at other locations and sent to CEDAP, where they are
processed, analyzed, and diagnosed.

As for cytology, only bladder washing samples were considered, excluding voided urine samples,
previously diagnosed as low-grade urothelial neoplasms and as high-grade urothelial carcinomas.
All cytology samples were prepared by CytoSpin and liquid cytology technique using the CellPrep
Plus diagnostic system (Biodyne, Seomgnam, Korea). This equipment is an automatic diagnostic

5
system for liquid cytology preparation of gynecological and non-gynecological samples. Samples
are collected into a preservative solution and further processed in the equipment. Cellular debris
in the samples is removed and a thin layer of cells is deposited on a slide – the cells are uniformly
distributed on the slide in monolayer, without cell overlapping and three-dimensionality, allowing
the preservation of cell morphology and thus good cell visualization and diagnostic accuracy (22).

The same analyses were stained by the Papanicolaou method, which consists of a multichromatic
staining cytological technique developed by George Papanikolaou, used to differentiate cells in
smear preparations of various biological secretions. It provides well-stained nuclear chromatin,
differential polychromatic counterstaining of the cytoplasm and cytoplasmatic transparency. It
requires the fixation of the smear to maintain the cytomorphologic characteristics and
diagnostically essential elements of the cell. The routine fixative used is 95% ethanol. This staining
technique consists of a nuclear dye, Gill Hematoxylin, an alkaline dye that binds to acidic
structures - stains the nuclei dark blue – and two cytoplasmatic counterstaining dyes: Orange G6 –
stains the keratin in the cytoplasm a brilliant orange, yellow or brown – and Eosin Azur –
composed by Eosin Y and Light Green SF; Eosin Y stains the cytoplasm of superficial cells in various
shades of pink and Light Green SF stains the cytoplasm of metabolically active cells, such as
parabasal and intermediate cells, histiocytes, columnar and malignant cells from pale to deep
green (23).

Regarding histology, all samples were fixed, processed, included and segmented by microtomy
into slides. The slides were posteriorly stained by Hematoxylin Eosin, a staining technique
consisting of an alkaline nuclear dye, Hematoxylin, that will stain the nuclei dark blue, and an
acidic cytoplasmic dye, Eosin, with affinity for alkaline structures such as the cytoplasm and cell
proteins, staining them in various shades of pink (24).

Task 6: Statistical analysis and organization of the gathered data

Description: After collecting all the samples and all the statistical and clinicopathological data
mentioned above, these will be further explored in the statistical software IBM SPSS 28.0.0.0,
developed by International Business Machines (IBM), which will allow the elaboration of a
database and the extraction of important statistics for the investigation. These statistics, based on
a confidence level of 95% and a margin of error of 5%, will allow the determination of the
agreement between samples classified as benign and malignant according to cytological and
histological analysis and the determination of Cohen's Kappa index of agreement between the
two. The non-parametric statistical test of the Chi-square of Independence will also be applied to
determine Odds Ratio statistical measures of association between the age and gender of the
patients to the different degrees of urothelial lesion, and also diagnostic measures important for
urinary cytology, such as sensitivity, specificity, accuracy and predictive values (positive and
negative), as well as the likelihood ratios.

Task 7: Elaboration and defense of the scientific paper

Description: Once completed all the tasks mentioned so far and collected all the necessary
information and data, it will be possible to start writing the final article, in which will be

6
mentioned the whole procedure and the conclusions acquired. The goal of this scientific article is
to be able to establish a correlation between the benignity and malignancy identified on cytology
with histological diagnosis, since the latter is the standard method of diagnosis of bladder cancers,
and to recognize the importance of histological analysis when diagnosing such cancers.

2.4 – Tasks
(max. 10000 characters without space) 2143
Task 1: Scientific information research

All information gathered is accessible in the PubMed/MEDLINE database and the literature
mentioned were all published between 2015 and the current date.

Task 2: Selection and characterization of the sample for the research study

A minimum of 60 individuals over the age of 35 years with previous clinical information or
suspicion of bladder disease from January 2022 to May 2023 will be selected. Only LGUN and
HGUC diagnosed samples will be considered.

Task 3: Submitting the project to the Ethics Committee of the Polytechnic Institute of Coimbra

The clinicopathological and statistical data will only be collected after the approval and
authorization from the CEIPC to conduct the research.

Task 4: Collection of clinicopathological and statistical data given from CEDAP in a population of
patients

As relevant information, the following data will be collected: gender, age and clinical history, as
these are factors for predisposition to urothelial pathology.

Task 5: Laboratory processing of cytological and histological samples

As for cytology, only bladder washing samples previously diagnosed as low-grade urothelial
neoplasms and as high-grade urothelial carcinomas were considered. All cytologic samples were
prepared by CytoSpin and liquid cytology technique using the CellPrep Plus diagnostic system
(Biodyne, Seomgnam, Korea) and stained by the Papanicolaou method.

All histologic samples were fixed, processed, included and segmented by microtomy into slides,
which were posteriorly stained by Hematoxylin Eosin stain.

Task 6: Statistical analysis and organization of the gathered data

After collecting all the samples and all the statistical and clinicopathological data mentioned
above, these will be further explored in the statistical software IBM SPSS 28.0.0.0, developed by
International Business Machines (IBM), which will allow the elaboration of a database and the
extraction of important statistics for the investigation. The statistical analysis of the correlation

7
between the results of cytological and histological diagnosis will enable the evaluation of the
sensitivity and specificity of urinary cytology to detect benign or malignant lesion by analyzing the
concordance between the results of both diagnostic methods.

Task 7: Elaboration and defense of the scientific paper

Once all the tasks mentioned above have been completed, the scientific paper will be developed,
where all the results and conclusions will be stated and discussed.

2.5 – Ethical Commission

(max. 10000 characters without space) 321
The project has been submitted to the Ethics Committee of the Polytechnic Institute of Coimbra,
and therefore its response and approval is pending. The collection of clinical and statistical data
from patients and, consequently, the statistical analysis and organization of these data and the
progression of the research study will only be conducted after approval by the CEIPC.

8
2.6 – Project Management and Planning

Title:
Urine cytology – Low-grade Urothelial Neoplasm and High-
grade Urothelial Lesion. Cytohistological correlation. 2022 2023
Task Nº Task designation Responsible 1 2 3 4 5 6 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 10 11 12

1 Scientific Information Research DO

2 Characterization of the sample DC, DO, PA, VS

Submission of the Project to the Ethics

3 DO
Committee of Polytechnic Institute of Coimbra

4 Collection of Clinicopathological and Statistical Data DC

Laboratory Processing of Cytological and Histological

5 DC
Samples

6 Statistical Analysis and Data Organization DO

7 Elaboration of the Scientific Paper DO

M1 M2 M3 M4

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3 – Research Team

Team Researcher Category Responsibilities

Daniela Oliveira Student Principal Investigator;

Data Analysis and
Organization; Scientific
Paper Writing
Paula Agapito CFIAC, ECTP (Gyn), TSDT Pathological Anatomy Tutor; Sample
Specialist, Coordinator at SAP, CHUC; Invited Characterization;
Adjunct Professor; Senior Cytotechnologist at Cytological Diagnosis
CEDAP
Laboratory Vítor de Sousa Teaching Pathologist at the Faculty of Co-tutor; Sample
Medicine, Pathologist at SAP, CHUC; Characterization;
Pathologist at CEDAP Cytological and
Histological Diagnosis
Daniel Coelho TSDT in Pathological Anatomy Collection of clinical
and statistical data;
Laboratory processing
of cytological and
histological samples
Rui Oliveira Professor and CEDAP Technical Director Histological Diagnosis

Daniela Oliveira Student Principal Investigator;

Data Analysis and
Statistic
Organization; Scientific
Paper Writing
João Figueiredo Professor at ESTeSC Data collection,
processing and analysis

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Equipa de Investigação:

Daniela Oliveira, Principal Professor Paula Agapito, Tutor

Investigator

Doctor Professor Vítor de Sousa, Daniel Coelho

Co-Tutor

Doctor Professor João Paulo Doctor Professor Rui Oliveira

Figueiredo

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