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\begin{document}

\title{Extrarenal Wilms tumor with hypertension and dilated cardiomyopathy in
an infant: A case report and review of the literature}



\author[1]{yanning Qu}%
\author[1]{Yurui Wu}%
\author[1]{Dong Qu}%
\author[1]{Haiyan Ge}%
\affil[1]{Capital Institute of Pediatrics}%


\vspace{-1em}



  
  \date{June 14, 2024}


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\selectlanguage{english}
\begin{abstract}
While Wilms tumors are the most frequently detected renal cancer type in
children, extrarenal Wilms tumors (ERWTs) remain rare. This report is
the first to describe hypertension and dilated cardiomyopathy in a
patient with an ERWT. A six-month-old male infant presented with an
abdominal mass and paroxysmal hypertension, echocardiography revealed
dilated cardiomyopathy with an ejection fraction of 34\%, as well as
substantially increased plasma renin activity. Pathology yielded a
definitive diagnosis of ERWT. Cardiac function and blood pressure
gradually returned to normal after tumorectomy. The early diagnosis of
such a tumor together with efficient oncologic treatment are vital to
optimal patient outcomes.%
\end{abstract}%



\sloppy


\textbf{Title page}

\textbf{Extrarenal Wilms tumor with hypertension and dilated
cardiomyopathy in an infant: A case report and review of the literature}

Yan-ning Qu\textsuperscript{1}, Yu-rui Wu\textsuperscript{2}, Dong
Qu\textsuperscript{1}, Hai-yan Ge\textsuperscript{1}

\textsuperscript{1}Department of Intensive care unit, Capital institute
of pediatric Children's hospital, Beijing 100021, China

\textsuperscript{2}Department of Thoracic and oncological surgery,
Capital institute of pediatric Children's hospital, Beijing 100021,
China

\textbf{Correspondence}

Dong Qu, Department of Intensive care unit, Capital institute of
pediatric Children's hospital, NO.2 Yabao street, Chaoyang district,
Beijing 100021, China. Phone: +86-010-85695612, Fax: +86-010-85695616.

Email: \emph{qudong2012@126.com}

\textbf{Word count for abstract:} 102

\textbf{Word count for main test:} 1752

\textbf{The number of Figures:} 2

\textbf{Running title:} ERWT with hypertension and dilated
cardiomyopathy

\textbf{Key words:} Extrarenal Wilms tumor (ERWT); Hypertension; Dilated
cardiomyopathy; Congestive heart failure (CHF); Case report.

\textbf{Abbreviations table}\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
\textbf{Abbreviation} & \textbf{Full term}\tabularnewline
\midrule
\endhead
ERWT & Extrarenal Wilms tumors\tabularnewline
CHF & Congestive heart failure\tabularnewline
ICU & Intensive care unit\tabularnewline
BP & Blood pressure\tabularnewline
MRI & Magnetic resonance imaging\tabularnewline
CT & Computed tomography\tabularnewline
\bottomrule
\end{longtable}

\textbf{Abstract}

While Wilms tumors are the most frequently detected renal cancer type in
children, extrarenal Wilms tumors (ERWTs) remain rare. This report is
the first to describe hypertension and dilated cardiomyopathy in a
patient with an ERWT. A six-month-old male infant presented with an
abdominal mass and paroxysmal hypertension, echocardiography revealed
dilated cardiomyopathy with an ejection fraction of 34\%, as well as
substantially increased plasma renin activity. Pathology yielded a
definitive diagnosis of ERWT. Cardiac function and blood pressure
gradually returned to normal after tumorectomy. The early diagnosis of
such a tumor together with efficient oncologic treatment are vital to
optimal patient outcomes.

\textbf{1 \textbar{} INTRODUCTION}

Wilms tumor, also referred to as nephroblastoma, accounts for
\textasciitilde{}90\% of all pediatric renal
malignancies\textsuperscript{{[}1{]}}. However, extrarenal Wilms tumor
(ERWT) manifestation remains rare, occurring in approximately 3\% of all
Wilms tumor cases\textsuperscript{{[}2{]}}. Such extrarenal tumors
typically present in the form of an asymptomatic mass within the
abdomen, although they can be accompanied by abdominal pain, hematuria,
and/or hypertension, with each occurring in roughly a quarter of such
cases\textsuperscript{{[}3{]}}. Dilated cardiomyopathy and congestive
heart failure (CHF) are rare presentations for such tumors, with only a
few previously reported cases exhibiting these symptoms. There have not
been any published reports to date of a case of ERWT presenting with
hypertension, dilated cardiomyopathy, and CHF. Here we present the first
case of ERWT with these rare symptoms and review the relevant
literature.

\textbf{2 \textbar{} CASE DESCRIPTION}

Our patient is a six-month-old male infant. He was found to exhibit
right cryptorchidism after birth, and one month ago his parents took him
to see a doctor because of this cryptorchidism. During the doctor's
examination, a mass was discovered in the lower abdomen, and the patient
was therefore admitted to the Department of Thoracic and oncological
surgery of our hospital for further examination and treatment. However,
just after hospitalization, the patient exhibited progressive
hepatomegaly, dyspnea, paroxysmal tachycardia, and paroxysmal
hypertension, that had not been previously detected. Chest radiography
revealed cardiomegaly, and echocardiography revealed cardiomyopathy with
an ejection fraction of 34\%. The patient was diagnosed with acute heart
failure and treated using digoxin, milrinone, furosemide, and
spironolactone, which failed to resolve these symptoms. He was therefore
transferred to the intensive care unit (ICU) due to acute heart failure,
hypertension, and poor left ventricular contractility.

After transferring to the ICU, The patient exhibited a heart rate of 160
beats per minute, a respiratory rate of 55 breaths per minute, 100\%
blood oxygen saturation, and the blood pressure (BP) was 134/102 mmHg.
Cardiac examinations revealed grade II systolic murmur, low heart sound,
and a regular rhythm. A hard 5 cm x 5 cm x 4 cm mass was detected within
the lower right abdomen upon palpation. The liver was palpated 3 cm
below the right costal margin. We performed a series of laboratory
tests, and blood chemistry analyses revealed elevated levels of liver
enzymes (aspartate aminotransferase 417.2 U/L, normal: 0-40 U/L; alanine
aminotransferase 351.5 U/L, normal: 0-40 U/L), elevated troponin T
(348.8 ng/L, normal:[?] 14 ng/L), and markedly elevated pro-B-type
natriuretic peptide (\textgreater{}35000 pg/mL, normal: \textless{} 646
pg/mL). Substantial increases were also detected in plasma renin
activity (684.7 \selectlanguage{greek}µ\selectlanguage{english}IU/mL, normal: 3.11-41.2 \selectlanguage{greek}µ\selectlanguage{english}IU/mL), angiotensin I (18.74
ng/mL/hr, normal 0.15-2.33 ng/mL/hr ), angiotensin II (76.78 ng/mL/hr,
normal 25-60 ng/mL/hr ), and plasma aldosterone (2000 pg/mL, normal:
30-160 pg/mL). Plasma metanephrine levels were within the normal range
(1615.9 pmol/L, normal: 413.9-4434.2 pmol/L), and low urinary
metanephrine levels were detected (3 nmol/d, normal: 68.9-378 \selectlanguage{greek}µ\selectlanguage{english}g/d).
Cardiomegaly and diffuse pulmonary infiltration were detected through
chest radiographic imaging (Fig. 1A), with echocardiography revealing
dilated cardiomyopathy with an ejection fraction of 38.4\%, a shortening
fraction of 18.1\%, grade 2 mitral regurgitation, and no evidence of
intracardiac thrombus or heart defects (Fig. 1C). Abdominal magnetic
resonance imaging (MRI) revealed an inhomogeneous quasi-circular soft
tissue mass (48.7 mm \selectlanguage{ngerman}× 49.5 mm × 52.8 mm) (Figs. 1E and 1F), ascites,
and bilateral pleural effusion.

The patient underwent emergency ICU treatment for CHF, hypertension, and
left ventricular dysfunction with oral digoxin, spironolactone and
intravenous milrinone and furosemide. However, owing to elevated
renin-angiotensin-aldosterone levels, BP control was difficult. When the
patient was treated with low-dose captopril (0.3 mg/kg), he developed
severe hypotension, with BP dropping from 134/75mmHg to 69/32mmHg within
30 minutes and the drug was immediately discontinued. Antihypertensive
drugs were then exchanged for urapidil and then sodium nitroprusside,
with BP gradually returning to the normal range. However, there was
still an occasional paroxysmal increase in BP. Owing to dyspnea,
non-invasive ventilation was required to provide breathing assistance.
After all of these treatments, the patient exhibited improved left
ventricular ejection fraction (LVEF; from 34\% to 58\%) and BP (from
158/110mmHg to 117/68mmHg). After hemodynamic stabilization had largely
been achieved, the mass was resected through an open surgical procedure
on day 22 of hospitalization.

Pathologic examination revealed a well-circumscribed 6.0 cm x 5.0 cm x
5.0 cm mass consistent with ERWT without anaplasia (Fig. 2A).
Microscopic analyses revealed triphasic histological findings
characteristics of a Wilms tumor, including stromal, epithelial, and
renal blastema elements. Testicular tissue was observed covering the
tumor surface intraoperatively, but there was no evidence of tumor
invasion of the surrounding tissues, including epididymal or testicular
tissue. Embryonic renal tissue remnants were observed around the tumor.
The tumor exhibited positive immunohistochemical staining for WT-1 (Fig.
2B), EGFR, CK19, AE1/AE3, and CAM5.2.

Postoperatively, the patient's BP returned to the normal range and
antihypertensive drugs were discontinued immediately following surgery,
whereupon BP remained stable. Plasma renin activity returned to the
normal range within one day postoperatively, and cardiac size and
function returned to normal within 24 days after surgery (Fig. 1B and
1D). He is currently undergoing adjuvant chemotherapy treatment
(vincristine, doxorubicin, and actinomycin D) as per the recommendations
of the International Society of Pediatric Oncology
(SIOP)\textsuperscript{{[}4{]}} at a local hospital.

A follow-up was conducted in our hospital two months after surgery.
Cardiotonic drug use was gradually tapered until being fully
discontinued, and the patient's heart rate, BP, and cardiac function
have since remained stable. To date, it has been 4 months since the
operation, and a recent telephone follow-up indicated that he has
undergone four courses of chemotherapy and remains in stable condition.
Additionally, his chest and abdominal computed tomography (CT) scans
performed at a local hospital have shown no evidence of recurrence four
months after treatment.

\textbf{3 \textbar{} DISCUSSION}

Given their rarity, accurately diagnosing ERWTs prior to surgical
resection remains challenging. The primary diagnosis in the present case
was pheochromocytoma owing to the observed paroxysmal tachycardia and
hypertension, but the normal urinary and plasma catecholamine levels did
not support this diagnosis. We also considered neuroblastoma, as about
10\% of neuroblastoma cases present with high
BP\textsuperscript{{[}5{]}}, and there have also been case reports of
neuroblastoma with hypertension and dilated cardiomyopathy, suggesting
that this tumor type can cause the activation of the reninangiotensin
aldosterone system\textsuperscript{{[}6{]}.} However, about 90\% of
cases exhibited elevated urinary catecholamine
metabolites\textsuperscript{{[}7{]}}, which was not evident in the
present case. In addition to the above differential diagnosis, as some
of these tumors arise within the pelvis, they may be incorrectly
diagnosed as ovarian cysts or pelvic teratomas\textsuperscript{{[}8{]}},
but these rarely cause high blood pressure and heart failure. In
general, only postoperative pathological analyses ultimately lead to
definitive ERWT diagnoses. Per Beckwith and
Palmer\textsuperscript{{[}9{]}}, ERWTs are diagnosed based upon the
following criteria: a primary extrarenal tumor exhibiting a primitive
blastematous spindle or round cell component, with an abortive,
embryonal tubular, or glomeruloid structure and no evidence of teratoma
or renal carcinoma. WT1 is the most sensitive immunohistochemical marker
for Wilms tumor diagnosis, being detectable in \textgreater{} 90\% of
cases\textsuperscript{{[}10{]}}. Ultimately, in this medical record,
pathological results were instead consistent with an ERWT, with WT1
positivity being observed upon immunohistochemical staining, diagnosis
is definitive. Another rare aspect of this case is that the tumor arose
next to the undescended testis. There have only been a few prior reports
of paratesticular ERWTs to date\textsuperscript{{[}11{]}}.

To date, there have only been six published cases of Wilms tumor
patients suffering from hypertensive cardiomyopathy and subsequent
CHF\textsuperscript{{[}12-17{]}}, with all of these cases being tied to
primary intrarenal tumors. This report is the first to describe
hypertension and CHF in a patient with an ERWT. The two mechanisms that
are generally believed to contribute to hyperreninemia are Wilms
tumor-mediated renin production and the tumor-mediated compression of
the renal artery. Immunohistochemical staining of the tumor tissues from
five Wilms tumor patients revealed detectable renin expression in the
blastemal portion of the tumor tissue, supporting a model wherein the
production of renin by these tumors is the primary driver of
hypertension\textsuperscript{{[}18{]}}. In the present case,
preoperative renin levels were significantly elevated but rapidly
returned to normal ranges within the days following surgery. Moreover,
the tumor was located within the pelvis, thus precluding the potential
for renal artery compression. We thus speculate that this tumor was
capable of directly secreting renin, contributing to secondary
complications including dilated cardiomyopathy, hypertension, and CHF.
Tumor resection alleviated the observed deterioration in cardiac
function, with gradual postoperative improvements in LV contractility,
performance, and function. It is thus evident that tumor-induced
hyperreninemia led to increased angiotensin II and aldosterone,
resulting in hypertension and hypertensive cardiomyopathy. However,
Perry \emph{et al} \textsuperscript{{[}19{]}} reported cases of Wilms
tumors with dilated cardiomyopathy without hyperreninemia. They note
that in addition to renin, there may be other vasoactive mediators that
can contribute to dilated cardiomyopathy and CHF, but further research
will be required to confirm this possibility.

When assessing patients presenting with pelvic tumors complicated by
heart failure and hypertension, ERWTs must be considered in the
differential diagnosis. Hypertension can frequently lead to the
potential for misdiagnosis in these cases, underscoring the need to
raise awareness of this rare complication of such extrarenal tumors.
Preoperatively controlling BP is critical in the treatment of ERWTs
patients, and the use of angiotensin-converting enzyme inhibitors may
represent the most effective means of treating renin-mediated
hypertension in these patients prior to surgical
intervention\textsuperscript{{[}20{]}}. In the present case, the patient
exhibited pronounced hypotension following the administration of
low-dose captopril (0.3 mg/kg), suggesting that even lower doses should
be used in the future in an effort to prevent this complication. The
overall prognosis of ERWT patients is similar to that of intrarenal
Wilms tumor patients, with surgical resection of the tumor representing
the most effective means of controlling tumor growth and associated
complications. Following tumorectomy, the prognosis of affected patients
is generally good. However, in patients presenting with unexplained
pelvic or abdominal tumors, early diagnosis and prompt surgical
intervention are recommended to prevent or mitigate hypertension,
dilated cardiomyopathy, and heart failure, thus contributing to a better
patient prognosis.

\textbf{4 \textbar{} CONCLUSION}

ERWTs should be considered in the differential diagnosis of children
exhibiting a pelvic mass and suffering from hypertension and dilated
cardiomyopathy. The clinical symptoms observed in the present case were
likely attributable to the secretion of renin by the Wilms tumor. Tumor
resection represents a highly effective treatment for affected patients,
but ERWTs presenting with CHF and dilated cardiomyopathy are nonetheless
life-threatening, underscoring the need for early diagnosis and the
timely provision of intensive care and oncological treatment in order to
ensure the best possible clinical outcomes.

\textbf{CONFLICTS OF INTEREST}

The authors declare no conflict of interests for this manuscript.

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\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

\textbf{FIGURE 1} Imaging examination. (A) X-ray imaging revealed
cardiomegaly, with diffuse bilateral increased pulmonary opacity; (B)
Following treatment for one month (one-week post-surgery), X-ray imaging
revealed mild cardiomegaly less severe than previously noted with the
disappearance of lung infiltrates; (C) Echocardiography revealed a
hypokinetic left ventricle with an ejection fraction of 38.4\% and
fractional shortening of 18.1\%, the left ventricular diastolic diameter
(LVDd) was 34.8mm; (D) 24 days after operation, echocardiography
exhibited normal cardiac function with an ejection fraction of 60.4\%
and fractional shortening of 30.9\%; the LVDd had reverted to 27.2mm;
(E-F) MRI revealed an inhomogeneous quasi-circular 48.7 mm \selectlanguage{ngerman}× 49.5 mm ×
52.8 mm soft tissue mass.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

\textbf{FIGURE 2} Histological results. (A) Histological by
hematoxylin-eosin staining analyses of tumor sections revealed stromal,
epithelial, and renal blastema elements within the tumor (200\selectlanguage{ngerman}×) (scale =
50 \selectlanguage{greek}μ\selectlanguage{english}m); (B) The tumor exhibited positive immunohistochemical staining
for WT-1 (200\selectlanguage{ngerman}×) (scale = 50 \selectlanguage{greek}μ\selectlanguage{english}m).\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-1/Figure-1}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/figure-2/figure-2}

\end{center}
\end{figure}

\selectlanguage{english}
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