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\begin{document}

\title{Programmed Death Cell Ligand-1 Expression in Lymphoepithelioma-like
Carcinoma of the Bladder: A Case Report}



\author[1]{Ahmet Serdar Teoman}%
\author[2]{Hatice Kucuk}%
\author[2]{Gizem Teoman}%
\affil[1]{Trabzon Fatih State Hospital}%
\affil[2]{SUB Kanuni Training and Research Hospital}%


\vspace{-1em}



  
  \date{May 24, 2024}


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\selectlanguage{english}
\begin{abstract}
Introduction: Lymphoepithelioma-like carcinoma of the bladder (LELC-B)
is a rare variant of bladder tumors and until today only 145 cases are
reported in the literature. It has a worse prognosis and survival rates
in comparison with papillary muscle invasive tumors. However, general
treatment options including radical cystectomy, chemotherapy and
radiotherapy; discovery of the programmed death cell ligand-1 (PDL-1)
expression for LELC-B recently, may lead a novel immunohistochemical
diagnostic method and PDL-1 immunostaining may increase detection of
this variant. Case Presentation: A 72-year-old male patient with lower
urinary tract symptoms is diagnosed as bladder tumor with imaging
modalities. After transurethral resection of this bladder tumor,
immunopathological diagnose was muscle invasive bladder tumor
predominantly lymphepithelioma like carcinoma of the bladder. PDL-1
immunostaining was also highly positive(\textgreater{}\%50).
Discussion/Conclusion: Lymphoepithelioma-like cancer of bladder is an
undifferantiated aggressive rare variant of bladder cancers. Its
identifiability may increase with detection of PDL-1 expression. In the
future, that might pave a road to targeted immunotherapies as an
alternative for selected patients.%
\end{abstract}%



\sloppy


Programmed Death Cell Ligand-1 Expression in Lymphoepithelioma-like
Carcinoma of the Bladder: A Case Report

Ahmet Serdar TEOMAN\textsuperscript{1}*, Hatice
KUCUK\textsuperscript{2}and Gizem TEOMAN\textsuperscript{2}

\textsuperscript{1} Urology Clinic, Trabzon Fatih State Hospital,
Trabzon, Turkey;\textsuperscript{2} Pathology Department, Kanuni
Training and Research Hospital, Trabzon, Turkey

\textbf{Running Title: PDL-1 Expression in LELC-B}

*\emph{Corresponding author:} Ahmet Serdar TEOMAN, MD, FEBU

Trabzon Fatih State Hospital, Urology Clinic

Trabzon, TURKEY

Tel: +90 (533) 3873874

e-mail: \emph{asteoman88@gmail.com}

\textbf{Word Counts} :

Abstract: 170 words

Main text (with abstract): 1101 words

\textbf{Disclosures Relevant to this Paper:}

All the authors declare that there is no conflict of interest and no
financial support for this study.

\textbf{Abstract}

\textbf{Introduction}: Lymphoepithelioma-like carcinoma of the bladder
(LELC-B) is a rare variant of bladder tumors and until today only 145
cases are reported in the literature. It has a worse prognosis and
survival rates in comparison with papillary muscle invasive tumors.
However, general treatment options including radical cystectomy,
chemotherapy and radiotherapy; discovery of the programmed death cell
ligand-1 (PDL-1) expression for LELC-B recently, may lead a novel
immunohistochemical diagnostic method and PDL-1 immunostaining may
increase detection of this variant.\textbf{Case Presentation}: A
72-year-old male patient with lower urinary tract symptoms is diagnosed
as bladder tumor with imaging modalities. After transurethral resection
of this bladder tumor, immunopathological diagnose was muscle invasive
bladder tumor predominantly lymphepithelioma like carcinoma of the
bladder. PDL-1 immunostaining was also highly
positive(\textgreater{}\%50).\textbf{Discussion/Conclusion}:
Lymphoepithelioma-like cancer of bladder is an undifferantiated
aggressive rare variant of bladder cancers. Its identifiability may
increase with detection of PDL-1 expression that has not been mentioned
before. In the future, that might pave a road to targeted
immunotherapies as an alternative for selected
patients.\textbf{Keywords:} lymphoepithelioma-like cancer, bladder,
programmed death cell ligand-1, immunohistochemistry.\textbf{What is
known?}Lymphoepithelioma-like carcinoma of the bladder (LELC-B) is a
rare variant of bladder tumors and until today only 145 cases are
reported in the literature. It has a worse prognosis and survival rates
in comparison with papillary muscle invasive tumors. However, general
treatment options including radical cystectomy, chemotherapy and
radiotherapy; discovery of the programmed death cell ligand-1 (PDL-1)
expression for LELC-B recently, may lead a novel immunohistochemical
diagnostic method and PDL-1 immunostaining may increase detection of
this variant.\textbf{What is new?}In this case we showed PDL-1
expression in a rare tumor- lymphoepitelioma-like bladder cancer- that
was only mentioned in one study in the literature. We believe, this
short report may contribute to the
literature.\textbf{Introduction}Bladder cancer is seventh commonly
diagnosed cancer in men, and when both genders are considered, its
ranking drops to eleventh {[}1{]}\textsuperscript{.} More than \%90
cases are urothelial carcinoma and the rest of them are the variant
histology that was described in 2016 WHO classification of tumours based
on 2004 classification {[}2{]}. Lymphoepithelioma-like carcinoma of the
bladder (LELC-B) is a rare variant and was first described in 1991 with
five cases that were mimicking lymphoma {[}3{]}. Histological appearance
of LELC-B closely resembles lymphoepithelioma of the nasopharynx.
Despite existence on histological appearance of Epstein-Barr virus (EBV)
positivity in nasopharynx, it has not detected in bladder {[}4{]}.
LELC-B is managed with radical cystectomy, chemotherapy or radiotherapy
after daignostic and therapeutic transurethral resection of bladder
tumor (TUR-BT) . Discovery of the programmed death cell ligand-1 (PDL-1)
expression in LELC-B may become significant for immunohistochemical
diagnosis and prognosis of the tumor and for patients, and implies
recent promising immune checkpoint targeted therapies
{[}5{]}\textsuperscript{.}Herein, we report a LELC-B case that shows
PDL-1 positive immunostaining that was not mentioned before in the
literature case reports to make contribution to the literature with a
new molecular diagnostic aspect to diagnose LELC-B more easily and to
get off the ground a new idea which might lead an alternative treatment
modality with targeting immune checkpoint control system for selected
patients.

\textbf{Case Report/Case Presentation}

A 72-year-old male patient presented to our urology clinic complaining
with lower urinary tract symptoms occurring for 2 months. He had
described no hematuria. An abdominopelvic ultrasound revealed that there
is a 4 cm in-diameter mass on the left lateral bladder wall with a
normal urinary tract. In patient's history, he had been operated one
year ago for bladder tumor (TUR-BT) and his pathology result had been
given as non-muscle invasive high grade papillary urothelial carcinoma.
A chest and abdominopelvic computed tomography did not show significant
lymph node involvement or any invasion. The patient underwent a
cystoscopy, which revealed a single non-papillary, solid large tumor
morphology, located on the left lateral bladder wall. An extensive
TUR-BT was performed in a single session. Postoperative
3\textsuperscript{rd} day, he was discharged from hospital without any
complication. Histological study showed that a urothelial carcinoma
predominantly infiltrated muscle layer of bladder with large cells with
eosinophilic cytoplasm and atypical nucleolated nuclei. Syncytial
clusters of undifferentiated highly vesicular nucleolus nucleus cells
bathed in abundant lymphoid stroma (Figure 1). Pathology result was
given as muscle invasive urothelial carcinoma predominantly
lymphoepithelioma like cancer of bladder (LELC-B). Immunohistochemical
study with mismatch repair proteins (MLH1, MSH2, MSH6 and PMS2) (Cell
Marque, Rocklin) showed no loss of expression, so that microsatellite
instability possibility was found low in tumor cells (Figure 2a-d). EBV
staining (EBER1) was negative and PDL-1 staining (SP263, Ventana, Roche)
was positive (Figure 2e). A second deeper resection for tumor site was
performed and pathology result was given asT2 tumor. With this
condition, radical cystectomy was offered to the patient. In spite of
the patient's refusal to radical cystectomy, he was consulted to medical
oncology department for further treatment. The patient was informed and
he has given written consent to publish this case report in accordance
to the Declaration of Helsinki.

\textbf{Discussion/Conclusion}

Lymphoepitheliomas are derived from nasopharynx and are associated with
Epstein Barr virus (EBV) infections. Lymphoepithelioma like carcinomas
are with similar histological features and originate outside
nasopharynx. They have been reported in the other sites including
prostate, breast, uterine cervix, skin, lung and bladder {[}2{]}. It was
first reported by Zukerberg et al. and in the literature 145 cases were
reported until 2018 {[}2,3{]}\textsuperscript{.}According to the latest
PubMed review of LELC-B reporting cases between 1991 and 2016, this
entity is usually late-onset (mean age was given as seventh decade) and
has a male predominance (approximately 3:1)
{[}4{]}\textsuperscript{.}Until today, exact pathogenesis of this tumor
is not elucidated. Although the association between EBV and
lymphoepithelioma of nasopharynx, lung, thymus etc., in bladder, no
significant encoded RNA was found for EBV {[}4{]}\textsuperscript{.}
Differential diagnosis for LELC-B from urothelial carcinoma is crucial
because of its prognosis and treatment modalities. LELC-B is defined in
WHO 2016 classification of tumors as an undifferentiated urothelial
carcinoma subtype. However, pure and predominant (\textgreater{}\%50 of
tumor) LELC-B prognosis is worse {[}2{]}\textsuperscript{.}LELC-B is
treated with conventional therapies like TUR-BT, radical cystectomy,
chemotherapy, radiotherapy and combination of these therapies. In the
literature, case reports and reviews suggest that optimal therapy is
radical cystectomy and adjuvant chemo/radiotherapy. Some studies offer
bladder preservative therapies for patients who do not accept with
radical cystectomy and chemo/radiotherapy in limited
circumstances{[}2{]}. A recent study that was conducted with 16 patients
with LELC-B, PDL-1 immunohistochemistry was performed and had determined
tumor cell staining were meaningfully positive for PDL-1 (most of them
had showed highly positive). This study concludes with immune checkpoint
inhibitors for bladder cancer, knowing the immune profile of the tumor
may have been pertinent in treatment decision making. The robust
lymphocytic infiltrate in LELC-B may be predictive as immune checkpoint
blockade therapies may have been second line therapies for muscle
invasive bladder cancers {[}5{]}\textsuperscript{.} In our case, PDL-1
immunostaining was highly positive (more than \%50) and the patient did
not comply with the conventional therapies. In the future in the light
of literature data, PDL-1 targeted therapies that were approved and
carried into practice might be an option for the patients like our case.
As a result, lymphoepithelioma-like cancer of bladder is an
undifferantiated rare variant tumor of bladder cancers. Its
identifiability may increase with detection of PDL-1 expression that
might pave a road to targeted immunotherapies as an alternative for
selected patients in the future.\textbf{Acknowledgements}The authors
certify that there is no conflict of interest with any financial
organization regarding the material discussed in the manuscript\emph{.}
This study was conducted with no funding resorces or a related funding
organisation

\section*{References}

{\label{references}}

{[}1{]} Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, Rosso S,
Coebergh JWW, Comber H, et al. Cancer incidence and mortality patterns
in Europe: estimates for 40 countries in 2012. Eur J Cancer
2013;49:1374--403. https://doi.org/10.1016/j.ejca.2012.12.027.

{[}2{]} Chaker K, Sellami A, Ouanes Y, Jallouli W, Chehida MA Ben, Abid
K, et al. About a case of lymphoepithelioma-like carcinoma of the
bladder. Urol Case Reports 2018;18:48--9.
https://doi.org/10.1016/j.eucr.2018.03.002.

{[}3{]} Zukerberg LR, Harris NL, Young RH. Carcinomas of the urinary
bladder simulating malignant lymphoma. A report of five cases. Am J Surg
Pathol 1991;15:569--76.
https://doi.org/10.1097/00000478-199106000-00005.

{[}4{]} Yang AW, Pooli A, Lele SM, Kim IW, Davies JD, LaGrange CA.
Lymphoepithelioma-like, a variant of urothelial carcinoma of the urinary
bladder: a case report and systematic review for optimal treatment
modality for disease-free survival. BMC Urol 2017;17:34.
https://doi.org/10.1186/s12894-017-0224-4.

{[}5{]} Manocha U, Kardos J, Selitsky S, Zhou M, Johnson SM, Breslauer
C, et al. RNA Expression Profiling of Lymphoepithelioma-Like Carcinoma
of the Bladder Reveals a Basal-Like Molecular Subtype. Am J Pathol
2020;190:134--44. https://doi.org/10.1016/j.ajpath.2019.09.007.

\textbf{Figure Legends}

Fig. 1. Predominantly infiltrated muscle layer of bladder with large
cells with eosinophilic cytoplasm and atypical nucleolated nuclei.
Syncytial clusters of undifferentiated highly vesicular nucleolus
nucleus cells bathed in abundant lymphoid stroma. (H\&E x200)

Fig. 2. \textbf{:} Mismatch repair protein immunohistochemistry was
found positive with a) MLH-1 (x100) b) MSH-2 (x100) c) MSH-6 (x100) d)
PMS-2 (x100) e) PDL-1 immunostaining was positive (x200).\selectlanguage{english}
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